HK1212347A1

HK1212347A1 - NOVEL TRICYCLIC 3,4-DIHYDRO-2H-PYRIDO[1,2-α]PYRAZINE-1,6-DIONE DERIVATIVES AS GAMMA SECRETASE MODULATORS

Info

Publication number: HK1212347A1
Application number: HK16100323.0A
Authority: HK
Inventors: François Paul BISCHOFF; Henricus Jacobus Maria Gijsen; Frans Alfons Maria Van Den Keybus; Frederik Jan Rita Rombouts
Original assignee: Janssen Pharmaceutica Nv
Priority date: 2012-12-20
Filing date: 2013-12-19
Publication date: 2016-06-10
Also published as: EP2953949B1; US20150307496A1; CA2889249A1; EP2953949A1; CN104918938B; ES2608356T3; AU2013366668A1; US10112943B2; JP2016503775A; CN104918938A; WO2014096212A1; JP6275161B2; KR20150095638A; AU2013366668B2; KR102209418B1; CA2889249C

Abstract

The present invention is concerned with novel tricyclic 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione derivatives of Formula (I) wherein R1, R2, R3, R4, L, Y, Z and X have the meaning defined in the claims. The compounds according to the present invention are useful as gamma secretase modulators. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.

Description

Novel tricyclic 3, 4-dihydro-2H-pyrido [1,2-a ] pyrazine-1, 6-dione derivatives as gamma secretase modulators

Technical Field

The present invention relates to novel tricyclic 3, 4-dihydro-2H-pyrido- [1,2-a ] pyrazine-1, 6-dione derivatives useful as gamma secretase modulators. The invention further relates to processes for the preparation of such novel compounds, pharmaceutical compositions comprising said compounds as active ingredient as well as the use of said compounds as medicaments.

Background

Alzheimer's Disease (AD) is a progressive neurodegenerative disease characterized by loss of memory, cognition and behavioral stability. AD afflicts 6% -10% of the population over the age of 65 and up to 50% for the population over the age of 85. It is the leading cause of dementia and the third leading cause of death after cardiovascular disease and cancer. There is currently no effective treatment for AD. The total cost associated with AD in the united states is over $1000 billion per year.

The etiology of AD is not simple, however, it is associated with certain risk factors, including (1) age, (2) family history, and (3) head trauma; other factors include environmental toxins and low education. Specific neuropathological pathologies in the limbus and cerebral cortex include intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein and extracellular deposits of fibrous aggregates of amyloid β peptide (amyloid plaques). The major components of amyloid plaques are amyloid beta (a- β, a β or a β) peptides of various lengths. Its variant, A.beta.1-42-peptide (A.beta. -42), is believed to be the major causative agent of amyloid formation. Another variant is the A.beta.1-40-peptide (A.beta.40). A β is a proteolytic product of a precursor protein, β amyloid precursor protein (β -APP or APP).

The familial, early-onset, somatomicropic inherited forms of AD are associated with missense mutations in β -amyloid precursor protein (β -APP or APP) and the aging protein (presenilin) proteins 1 and 2. In some patients, late-onset forms of AD have been associated with the discovery of specific alleles of the apolipoprotein e (apoe) gene and, more recently, mutations in alpha 2-macroglobulin that may be correlated with at least 30% of the AD population. Despite this heterogeneity, all forms of AD exhibit similar pathological outcomes. Genetic analysis has provided the best clue for rational treatment of AD. All mutations discovered to date affect the qualitative or quantitative production of the amyloidogenic peptide, known as the a β -peptide (a β), specifically a β 42, and have given great support to the "amyloid cascade hypothesis" (Tanzi and Bertram, 2005, Cell 120, 545) for AD. The possible link between a β peptide production and AD pathology underscores the need for a better understanding of the mechanisms of a β production and for strong assurance of therapeutics that modulate a β levels.

The release of a β peptide is regulated by at least two proteolytic activities of the a β peptide, referred to as β -and γ -secretase cleavage at the N-terminus (Met-Asp bond) and C-terminus (residues 37-42), respectively. In this secretory pathway, there is evidence that β -secretase is first cleaved, leading to secretion of s-APP β (s β) and retention of an 11kDa membrane-bound carboxy-terminal fragment (CTF). The latter is believed to result in subsequent cleavage of the a β peptide by γ -secretase. In patients with certain mutations in the region of a particular gene encoded in a particular protein (the protein senescence), the amount of the longer isoform, a β 42, was selectively increased, and these mutations were associated with early-onset familial AD. Thus, many researchers believe that: abeta 42 is the main culprit of the onset of AD.

It is now clear that gamma-secretase activity cannot be attributed to a single protein, but is in fact associated with a combination of different proteins.

Gamma (γ) -secretase activity is present in a multi-protein complex containing at least four components: the mature polypeptide fragments include the mature polypeptide fragments of the human mature polypeptide, the mature polypeptide fragments of the human mature Polypeptide (PS) heterodimers, the slow protein (nicastrin), aph-1 and pen-2. The PS heterodimer is composed of amino-and carboxy-terminal PS fragments generated by endoproteolysis of the precursor protein. The two aspartates of the catalytic site are at the interface of this heterodimer. It has recently been proposed that the dumb protein acts as a gamma-secretase-substrate receptor. The functionality of other members of the gamma-secretase enzyme is unknown, but they are required for activity (Steiner, 2004. "Current Alzheimer Research 1 (3): 175-.

Thus, while the molecular mechanism of the second cleavage step has remained elusive to date, the γ -secretase-complex has become one of the major targets in the search for compounds for the treatment of AD.

Various Strategies have been proposed for targeting gamma-secretase in AD, ranging from direct targeting of catalytic sites, development of substrate-specific inhibitors and modulators of gamma-secretase activity (marqueen et al, 2004.: drug discovery: Therapeutic Strategies Today, Vol.1, 1-6). Thus, a number of compounds having secretase as a target have been described (Larner, 2004. secretase in AD as a therapeutic target: patents (Secretases as therapeutics targets in AD: patents)2000-2004. review of therapeutic patents (Expert Opin. patents)14, 1403-1420).

Indeed, this finding is supported by biochemical studies in which the effects of certain non-steroidal anti-inflammatory drugs (NSAIDs) on gamma-secretase have been shown (US 2002/0128319; Eriksen (2003) J.Clin. invest.)112, 440). Potential limitations for the use of NSAIDs for the prevention or treatment of AD are their Cyclooxygenase (COX) inhibitory activity, which can lead to unwanted side effects, and their low CNS penetration (by pelelto et al, 2005, journal of medicinal chemistry (j.med.chem.), 48, 5705-. More recently, NSAID R-flurbiprofen, an enantiomer lacking Cox-inhibiting activity and associated gastric toxicity, failed in large phase III trials because the drug did not significantly improve the patient's ability to think or ability to perform daily activities more than those of placebo.

WO-2010/100606 discloses phenylimidazoles and phenyltriazoles for use as gamma-secretase modulators.

US 20090062529 relates to polycyclic compounds useful as therapeutic or prophylactic agents for diseases caused by a β.

WO-2010/070008 relates to novel substituted bicyclic imidazole derivatives useful as gamma-secretase modulators.

WO-2010/089292 relates to novel substituted bicyclic heterocyclic derivatives useful as modulators of gamma-secretase.

WO-2011/006903 relates to novel substituted triazole and imidazole derivatives useful as modulators of gamma-secretase.

WO-2012/131539 relates to novel bicyclic pyridones useful as modulators of gamma-secretase of brain penetration.

There is a strong need for novel compounds that modulate gamma-secretase activity, thereby opening up new ways to treat AD. It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative. The compounds of the invention or portions of the compounds of the invention may have improved metabolic stability properties, improved availability to the brain center, improved solubility, or reduced CYP inhibition as compared to compounds disclosed in the prior art. It is therefore an object of the present invention to provide such novel compounds.

Summary of The Invention

The compounds of the present invention have been found to be useful as gamma secretase modulators. The compounds according to the invention, and their pharmaceutically acceptable compositions, are useful in the treatment or prevention of AD.

The present invention relates to novel compounds of formula (I)

Tautomers and stereoisomeric forms thereof, wherein

R¹Is phenyl, naphthyl, indolyl, benzothienyl, benzothiazolyl, or benzofuranyl;

each optionally substituted with one, two, or three substituents each independently selected from the group consisting of: halogen and C optionally substituted with one, two or three halogen substituents_1-4An alkyl group;

l is attached to position a or b;

l is selected from the group consisting of: covalent bond, -C_1-6Alkanediyl-and

-O-C_1-6alkanediyl-;

y is-Q- (CH)₂)_m-、-CH₂-Q-CH₂-、-(CH₂)_n-、

One of them being-CH₂-by hydroxy and C_1-4Alkyl substituted- (CH)₂)_n-, or

One of them being-CH₂-substituted by one hydroxy group- (CH)₂)_n-；

n represents 1,2 or 3;

m represents 1 or 2;

q is O or NR⁶；

R⁶Is hydrogen or C_1-4An alkyl group;

z is methylene or 1, 2-ethanediyl, wherein methylene or 1, 2-ethanediyl is optionally substituted by one or two C_1-4Alkyl substituent group substitution;

R²is hydrogen, halogen or C_1-4An alkyl group;

R³is hydrogen or C_1-4An alkyl group;

R⁴is hydrogen, halogen or C_1-4An alkyl group;

x is CR⁵Or N;

R⁵is hydrogen or C_1-4An alkyl group;

and pharmaceutically acceptable addition salts and solvates thereof.

The invention also relates to processes for the preparation of the compounds of the invention and pharmaceutical compositions comprising them.

The compounds of the invention are found to modulate gamma-secretase activity in vitro and in vivo and are therefore useful in the treatment or prevention of AD, Traumatic Brain Injury (TBI), dementia pugilistica, Mild Cognitive Impairment (MCI), senility, dementia with lewy bodies, cerebral amyloid angiopathy, multi-infarct dementia, down's syndrome, dementia associated with parkinson's disease and dementia associated with beta-amyloid; AD and other disorders with beta-amyloid pathologies (e.g., glaucoma) are preferred.

In view of the above-mentioned pharmacology of the compounds of formula (I) and their pharmaceutically acceptable addition salts and solvates, it follows that these compounds may be suitable for use as medicaments.

More particularly, these compounds of formula (I) and the pharmaceutically acceptable addition salts and solvates thereof may be suitable for the treatment or prevention of AD, cerebral amyloid angiopathy, multi-infarct dementia, dementia pugilistica and down syndrome.

The invention also relates to the use of a compound according to general formula (I), and the pharmaceutically acceptable acid or base addition salts and solvates thereof, for the manufacture of a medicament for the modulation of γ -secretase activity.

The invention will now be further described. In the following paragraphs, the different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any one or more other aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any one or more other features indicated as being preferred or advantageous.

Detailed Description

When describing the compounds of the present invention, the terms used are intended to be understood in accordance with the following definitions, unless the context dictates otherwise.

Whenever the term "substituted" is used in the present invention, unless otherwise indicated or clear from the context, it is meant to indicate that one or more hydrogens (in particular from 1 to 3 hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen) on the atom or group indicated in the expression using "substituted" is replaced by a selection from the indicated group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound (i.e. a compound that is robust enough to withstand separation from the reaction mixture to a useful degree of purity, and robust enough to withstand formulation with a therapeutic agent).

Unless otherwise indicated or clear from the context, the term "halogen" as a group or part of a group is generic to fluorine, chlorine, bromine, iodine.

The term "C" as a group or part of a group_1-4Alkyl "means having the formula C_nH_2n+1Wherein n is a number in the range of 1 to 4. C_1-4The alkyl group includes from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms, more preferably from 1 to 2 carbon atoms. C_1-4Alkyl groups may be linear or branched, and may be substituted as indicated herein. When a subscript is used herein after a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. C_1-4Alkyl includes all linear or branched alkyl groups having between 1 and 4 carbon atoms and thus includes, for example, methyl, ethyl, n-propyl, isopropyl, 2-methyl-ethyl, butyl and its isomers (e.g., n-butyl, isobutyl and tert-butyl), and the like.

The term "C" as a group or part of a group_1-6Alkanediyl "defines divalent straight-chain or branched saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example, methylene or methanediyl, ethane-1, 2-diyl, ethane-1, 1-diyl or ethylene, propane-1, 3-diyl, propane-1, 2-diyl, butane-1, 4-diyl, pentane-1, 5-diyl, pentane-1, 1-diyl, hexane-1, 6-diyl, 2-methylbutane-1, 4-diyl, 3-methylpentane-1, 5-diyl and the like.

Whenever the variable 'L' represents-O-C_1-6Alkanediyl-, which is intended to indicate that the oxygen is attached to' R¹' to and C_1-6The alkanediyl is attached at position a or b to the rest of the molecule. This is illustrated by formula (I'):

whenever the variable 'Y' represents-Q- (CH)₂)_m-, which is intended to indicate that Q is attached to the carbon atom in position b and (CH)₂)_mAttached to the carbon atoms to which the rings are fused. This is illustrated by formula (I "):

the chemical names of the compounds of the present invention were generated according to the nomenclature rules agreed upon by the chemical abstracts Service (chemical abstracts Service) using the advanced chemical Development (ACD/laboratory release 12.00Product version 12.01; Build 33104, 2009, 5 months and 27 days) company naming software. In the case of tautomeric forms, the name of the tautomeric form results. It must be clarified that other tautomeric forms not shown are also included in the scope of the present invention.

If L represents- (CH)₂)_nN represents 1 and Z is methylene, the atoms in the tricyclic system being numbered as agreed by Chemical Abstracts Service (Chemical Abstracts Service), as shown in the following formula (XX-a):

if L represents- (CH)₂)_nN represents 2 and Z is methylene, the atoms in the tricyclic system being numbered as agreed by Chemical Abstracts Service (Chemical Abstracts Service), as shown in the following formula (XX-b):

as used herein, the term "compounds of the present invention" is meant to include compounds of formula (I) and salts and solvates thereof.

As used herein, any formula having bonds that are shown only as solid lines and not as solid or dashed wedge bonds, or otherwise represented as having a particular configuration (e.g., R, S) around one or more atoms, contemplates each possible stereoisomer, or a mixture of two or more stereoisomers.

In this context, the term "compound of formula (I)" is meant to include its stereoisomers and its tautomeric forms.

The terms "stereoisomer", "stereoisomeric form" or "stereochemically isomeric form" are used interchangeably hereinabove or hereinbelow.

The present invention includes all stereoisomers of the compounds of the invention, either in pure stereoisomeric form or in a mixture of two or more stereoisomers.

Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A1: 1 mixture of enantiomeric pairs is a racemate or a racemic mixture.

Diastereomers (diastereomers) (or diastereomers) are stereoisomers of diastereomers, i.e., they are not related in mirror image form. If the compound contains a double bond, these substituents may be in the E or Z configuration. The substituents on the divalent cyclic (partially) saturated groups may have either the cis- (cis-) or trans- (trans-) configuration, for example, if the compound comprises a disubstituted cycloalkyl group, the substituents may be in either the cis or trans configuration. Thus, the present invention includes enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, as long as they are chemically possible.

The meaning of all those terms, i.e., enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof, are known to those of ordinary skill in the art.

The absolute configuration is specified according to the Kam-Yin Gao-prilor (Cahn-Ingold-Prelog) system. The configuration at the asymmetric atom is specified by R or S. Resolved stereoisomers whose absolute configuration is unknown can be designated (+) or (-) depending on the direction in which they rotate plane polarized light. For example, resolved enantiomers of unknown absolute configuration may be designated (+) or (-), depending on the direction in which they rotate plane polarized light.

When a particular stereoisomer is identified, this means that the stereoisomer is substantially free of, i.e., associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, specifically less than 2% and most preferably less than 1% of the other stereoisomers. Thus, when a compound of formula (I) is, for example, referred to as (R), this means that the compound is substantially free of the (S) isomer; when a compound of formula (I) is designated e.g. as E, this means that the compound is substantially free of Z isomer; when a compound of formula (I) is designated, for example, as cis, this means that the compound is substantially free of trans isomers.

Some compounds according to formula (I) can also exist in their tautomeric form. Although not explicitly indicated in formula (I) above, such forms, where they may be present, are intended to be included within the scope of the present invention.

It follows that a single compound may exist in stereoisomeric and tautomeric forms.

For therapeutic use, salts of compounds of formula (I) and solvates thereof are those wherein the counterion is pharmaceutically acceptable. However, salts of pharmaceutically unacceptable acids and bases may also find use, for example, in the preparation or purification of pharmaceutically acceptable compounds. All salts, whether pharmaceutically acceptable or not, are included within the scope of the invention.

Pharmaceutically acceptable acid addition salts and base addition salts as mentioned hereinbefore and hereinafter are meant to include therapeutically active non-toxic acid addition salt and base addition salt forms which the compounds of formula (I) and solvates thereof are able to form. Pharmaceutically acceptable acid addition salts may be conveniently obtained by treating the base form with such an appropriate acid. Suitable acids include, for example, inorganic acids such as hydrohalic acids (e.g., hydrochloric or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids such as, for example, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid (i.e., oxalic acid), malonic acid, succinic acid (i.e., succinic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, and the like. Conversely, the salt form may be converted to the free base form by treatment with a suitable base.

The compounds of formula (I) and solvates thereof containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Suitable base salt forms include, for example, ammonium salts, alkali and alkaline earth metal salts, such as lithium, sodium, potassium, magnesium, calcium salts, and the like, and salts with organic bases, such as primary, secondary and tertiary aliphatic and aromatic amines, such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline, and isoquinoline; benzathine (benzathine), N-methyl-D-glucamine, hydrabamine salt, and salts with amino acids such as, for example, arginine, lysine, and the like. Conversely, the salt form may be converted to the free acid form by treatment with an acid.

The term solvate includes hydrates as well as solvent addition forms which the compounds of formula (I) as well as pharmaceutically acceptable salts thereof are able to form. Examples of such forms are, for example, hydrates, alcoholates and the like.

The compounds of the invention, as prepared in the processes described below, can be synthesized in the form of mixtures of enantiomers, in particular racemic mixtures of enantiomers, which can be separated from each other according to analytical procedures known in the art. A method of separating the enantiomeric forms of the compounds of formula (I) and pharmaceutically acceptable addition salts and solvates thereof comprises liquid chromatography using a chiral stationary phase. The pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction proceeds stereospecifically. Preferably, if a particular stereoisomer is desired, the compound will be synthesized by preparative stereospecific methods. These processes will advantageously use enantiomerically pure starting materials.

In the framework of the present application, elements, especially when mentioned in relation to compounds according to formula (I), including all isotopes and isotopic mixtures of such elements, are naturally occurring or synthetically produced, in natural abundance or in isotopically enriched form. The radiolabeled compound of formula (I) may include a radioisotope selected from the group of:³H、¹¹C、¹⁸F、¹²²I、¹²³I、¹²⁵I、¹³¹I、⁷⁵Br、⁷⁶Br、⁷⁷br and⁸²br is added. Preferably, the radioisotope is selected from the group of:³H、¹¹c and¹⁸F。

as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. For example, "a compound" refers to one compound or more than one compound.

In one embodiment, the present invention relates to novel compounds of formula (I):

tautomers and stereoisomeric forms thereof, wherein

R¹Is phenyl, naphthyl, indolyl, benzothienyl, benzothiazolyl, or benzofuranyl;

l is attached to position a or b;

l is selected from the group consisting of: covalent bond, -C_1-6alkanediyl-and-O-C_1-6Alkanediyl-;

y is- (CH)₂)_n- (one of them-CH₂May be substituted by hydroxy and C_1-4Alkyl substituted), -Q- (CH)₂)_m-or-CH₂-Q-CH₂-；

n represents 1,2 or 3;

m represents 1 or 2;

q is O or NR⁶；

R⁶Is hydrogen or C_1-4An alkyl group;

R²is hydrogen, halogen or C_1-4An alkyl group;

R³is hydrogen or C_1-4An alkyl group;

R⁴is hydrogen, halogen or C_1-4An alkyl group;

x is CR⁵Or N;

R⁵is hydrogen or C_1-4An alkyl group;

and pharmaceutically acceptable addition salts and solvates thereof.

In one embodiment, the present invention relates to novel compounds of formula (I), tautomers, and stereoisomeric forms thereof, wherein:

R¹is phenyl, naphthyl or indolyl;

l is attached to position a;

y is-Q- (CH)₂)_m-、-CH₂-Q-CH₂-、-(CH₂)_n-、

One of them being-CH₂-by hydroxy and C_1-4Alkyl substituted- (CH)₂)_n-, or

One of them being-CH₂-substituted by one hydroxy group- (CH)₂)_n-；

n represents 1,2 or 3;

m represents 1 or 2;

q is O or NR⁶；

R⁶Is hydrogen or C_1-4An alkyl group;

z is methylene;

R²is hydrogen;

R³is hydrogen or C_1-4An alkyl group;

R⁴is hydrogen, halogen or C_1-4An alkyl group;

x is CH;

and pharmaceutically acceptable addition salts and solvates thereof.

R¹is phenyl, naphthyl, indolyl, benzothienyl, benzothiazolyl, or benzofuranyl;

each substituted with one, two, or three substituents each independently selected from the group consisting of: halogen and C optionally substituted with one, two or three halogen substituents_1-4An alkyl group;

l is attached to position a or b;

y is-Q- (CH)₂)_m-、-CH₂-Q-CH₂-、-(CH₂)_n-、

One of them being-CH₂-by hydroxy and C_1-4Alkyl substituted- (CH)₂)_n-, or

One of them being-CH₂-substituted by one hydroxy group- (CH)₂)_n-；

n represents 1,2 or 3;

m represents 1 or 2;

q is O or NR⁶；

R⁶Is hydrogen or C_1-4An alkyl group;

R²is hydrogen, halogen or C_1-4An alkyl group;

R³is hydrogen or C_1-4An alkyl group;

R⁴is hydrogen, halogen or C_1-4An alkyl group;

x is CR⁵Or N;

R⁵is hydrogen or C_1-4An alkyl group;

and pharmaceutically acceptable addition salts and solvates thereof.

In one embodiment, the present invention relates to novel compounds of formula (I), tautomers and stereoisomeric forms thereof, wherein

R¹Is phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of: halogen and C optionally substituted with one, two or three halogen substituents_1-4An alkyl group;

l is attached to position a; l is a covalent bond or C_1-6An alkanediyl group;

y is- (CH)₂)_n-；

n represents 1,2 or 3;

R²is hydrogen, halogen or C_1-4An alkyl group;

R³is hydrogen or C_1-4An alkyl group;

R⁴is hydrogen, halogen or C_1-4An alkyl group;

x is CR⁵Or N;

R⁵is hydrogen or C_1-4An alkyl group;

and pharmaceutically acceptable addition salts and solvates thereof.

l is attached to position a or b;

y is-Q- (CH)₂)_m-、-CH₂-Q-CH₂-、-(CH₂)_n-、

One of them being-CH₂-by hydroxy and C_1-4Alkyl substituted- (CH)₂)_n-, or

One of them being-CH₂-substituted by one hydroxy group- (CH)₂)_n-；

n represents 1,2 or 3;

m represents 1 or 2;

q is O or NR⁶；

R⁶Is hydrogen or C_1-4An alkyl group;

R²is hydrogen, halogen or C_1-4An alkyl group;

R³is hydrogen or C_1-4An alkyl group;

R⁴is hydrogen, halogen or C_1-4An alkyl group;

x is CR⁵Or N;

R⁵is hydrogen or C_1-4An alkyl group;

and pharmaceutically acceptable addition salts and solvates thereof.

R¹Is phenyl substituted with two substituents each independently selected from the group consisting of: halogen and C optionally substituted with three halogen substituents_1-4An alkyl group;

l is attached to position a;

l is selected from the group consisting of: covalent bond and-C_1-6Alkanediyl-;

y is- (CH)₂)_n-；

n represents 1 or 2;

z is methylene;

R²is hydrogen;

R³is hydrogen;

R⁴is C_1-4An alkyl group;

x is CR⁵；

R⁵Is hydrogen;

and pharmaceutically acceptable addition salts and solvates thereof.

R¹Is formed by two CF₃Substituent groupOr phenyl substituted with two Cl substituents;

l is attached to position a;

l is selected from the group consisting of: a covalent bond and a methylene group;

y is- (CH)₂)_n-；

n represents 1 or 2;

z is methylene;

R²is hydrogen;

R³is hydrogen;

R⁴is methyl;

x is CR⁵；

R⁵Is hydrogen;

and pharmaceutically acceptable addition salts and solvates thereof.

In one embodiment, the present invention relates to those compounds of formula (I) and pharmaceutically acceptable addition salts and solvates thereof, or any subgroup thereof, mentioned in any other embodiment, wherein R¹Is phenyl substituted with one, two or three substituents each selected from the group consisting of: halogen and C substituted by one, two or three halogen substituents_1-4An alkyl group;

in particular, R¹Is phenyl substituted with two substituents each independently selected from the group consisting of: halogen and C substituted by three halogen substituents_1-4An alkyl group; more particularly, R¹Is 3, 5-bis (trifluoromethyl) -phenyl or 3, 4-dichlorophenyl.

In one embodiment, the present invention relates to those compounds of formula (I) and pharmaceutically acceptable addition salts and solvates thereof, or any subgroup thereof, mentioned in any other embodiment, wherein n is 1 or 2.

In one embodiment, the present invention relates to those compounds of formula (I) and pharmaceutically acceptable addition salts and solvates thereof, or any subgroup thereof, mentioned in any other embodiment, wherein L is a covalent bond or methylene.

In one embodiment, the present invention relates to those compounds of formula (I) and pharmaceutically acceptable addition salts and solvates thereof, or any subgroup thereof, mentioned in any other embodiment, wherein L is a covalent bond or-C_1-6An alkanediyl group-.

In one embodiment, the present invention relates to those compounds of formula (I) and pharmaceutically acceptable addition salts and solvates thereof, or any subgroup thereof, mentioned in any other embodiment, wherein

R¹Is phenyl, naphthyl or indolyl; each substituted with one, two, or three substituents each independently selected from the group consisting of: halogen and C optionally substituted with one, two or three halogen substituents_1-4An alkyl group.

In one embodiment, the present invention relates to those compounds of formula (I) and pharmaceutically acceptable addition salts and solvates thereof, or any subgroup thereof, mentioned in any other embodiment, wherein Z is methylene.

In one embodiment, the present invention relates to those compounds of formula (I) and pharmaceutically acceptable addition salts thereof, and solvates thereof, or any subgroup thereof, mentioned in any other embodiment, wherein R²Is hydrogen.

In one embodiment, the present invention relates to those compounds of formula (I) and pharmaceutically acceptable addition salts thereof, and solvates thereof, or any subgroup thereof, mentioned in any other embodiment, wherein R²Is H.

In one embodiment, the invention relates to the chemosynthesis of those mentioned in any of the other embodimentsA compound and its pharmaceutically acceptable addition salts and solvates, or any subgroup thereof, wherein R³Is H.

In one embodiment, the present invention relates to those compounds of formula (I) and pharmaceutically acceptable addition salts and solvates thereof, or any subgroup thereof, mentioned in any other embodiment, wherein R⁴Is C_1-4Alkyl or halogen; in particular C_1-4An alkyl group; more particularly methyl.

In one embodiment, the present invention relates to those compounds of formula (I) and pharmaceutically acceptable addition salts and solvates thereof, or any subgroup thereof, mentioned in any other embodiment, wherein L is attached at position a.

In one embodiment, the invention relates to those compounds of formula (I) and pharmaceutically acceptable addition salts and solvates thereof, or any subgroup thereof, mentioned in any other embodiment, wherein X is CR⁵。

In one embodiment, the present invention relates to those compounds of formula (I) and pharmaceutically acceptable addition salts thereof, and solvates thereof, or any subgroup thereof, mentioned in any other embodiment, wherein R⁵Is H.

In one embodiment, the present invention relates to those compounds of formula (I) and pharmaceutically acceptable addition salts and solvates thereof, or any subgroup thereof, mentioned in any other embodiment, wherein X is CH.

In one embodiment, the present invention relates to those compounds of formula (I) and pharmaceutically acceptable addition salts and solvates thereof, or any subgroup thereof, mentioned in any other embodiment, wherein L is attached at position a or b; and L is selected from the group consisting of: covalent bond, -CH₂-or-O-CH₂-。

In one embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, such as those mentioned in any of the other embodimentsAn addition salt and a solvate, or any subgroup thereof, wherein L is attached at position a; and L is selected from the group consisting of: covalent bond, -CH₂-or-O-CH₂-。

In one embodiment, the present invention relates to those compounds of formula (I) and pharmaceutically acceptable addition salts and solvates thereof, or any subgroup thereof, mentioned in any other embodiment, wherein R¹Is phenyl, indolyl or naphthyl. In particular, R¹Is phenyl or indolyl; more particularly, wherein R¹Is indolyl;

thus, according to any one of the other embodiments, the phenyl, indolyl or naphthyl group is (optionally) substituted.

In one embodiment, the compound of formula (I) is selected from the group consisting of:

3- (3, 4-dichlorophenyl) -2,3,11,11 a-tetrahydro-8- (4-methyl-1H-imidazol-1-yl) -1H-pyrido [1,2-a ] pyrrolo [1,2-d ] pyrazine-5, 9-dione,

(3R, 11aR) -3- (3, 4-dichlorophenyl) -2,3,11,11 a-tetrahydro-8- (4-methyl-1H-imidazol-1-yl) -1H-pyrido [1,2-a ] pyrrolo [1,2-d ] pyrazine-5, 9-dione,

(3S, 11aR) -3- (3, 4-dichlorophenyl) -2,3,11,11 a-tetrahydro-8- (4-methyl-1H-imidazol-1-yl) -1H-pyrido [1,2-a ] pyrrolo [1,2-d ] pyrazine-5, 9-dione,

10- [3, 5-bis (trifluoromethyl) phenyl ] -6, 6a, 7, 8, 9, 10-hexahydro-3- (4-methyl-1H-imidazol-1-yl) -bipyridino [1, 2-a: 1 ', 2' -d ] pyrazine-4, 12-diones,

10- [3, 5-bis (trifluoromethyl) phenyl ] -6, 6a, 7, 8, 9, 10-hexahydro-3- (4-methyl-1H-imidazol-1-yl) -bipyridino [1, 2-a: 1 ', 2' -d ] pyrazine-4, 12-diones ((6aR, 10S) or (6aS, 10R)),

10- [3, 5-bis (trifluoromethyl) phenyl ] -6, 6a, 7, 8, 9, 10-hexahydro-3- (4-methyl-1H-imidazol-1-yl) -bipyridino [1, 2-a: 1 ', 2' -d ] pyrazine-4, 12-diones ((6aS, 10R) or (6aR, 10S),

3- [3, 5-bis (trifluoromethyl) phenyl ] -2,3,11,11 a-tetrahydro-8- (4-methyl-1H-imidazol-1-yl) -1H-pyrido [1,2-a ] pyrrolo [1,2-d ] pyrazine-5, 9-dione,

(3R, 11aR) -3- [3, 5-bis (trifluoromethyl) phenyl ] -2,3,11,11 a-tetrahydro-8- (4-methyl-1H-imidazol-1-yl) -1H-pyrido [1,2-a ] pyrrolo [1,2-d ] pyrazine-5, 9-dione,

(3S, 11aR) -3- [3, 5-bis (trifluoromethyl) phenyl ] -2,3,11,11 a-tetrahydro-8- (4-methyl-1H-imidazol-1-yl) -1H-pyrido [1,2-a ] pyrrolo [1,2-d ] pyrazine-5, 9-dione,

3- [ [3, 5-bis (trifluoromethyl) phenyl ] methyl ] -2,3,11,11 a-tetrahydro-8- (4-methyl-1H-imidazol-1-yl) -1H-pyrido [1,2-a ] pyrrolo [1,2-d ] pyrazine-5, 9-dione,

3- [ [3, 5-bis (trifluoromethyl) phenyl ] methyl ] -2,3,11,11 a-tetrahydro-8- (4-methyl-1H-imidazol-1-yl) -1H-pyrido [1,2-a ] pyrrolo [1,2-d ] pyrazine-5, 9-dione ((3R, 11aR) or (3S, 11aS)),

3- [ [3, 5-bis (trifluoromethyl) phenyl ] methyl ] -2,3,11,11 a-tetrahydro-8- (4-methyl-1H-imidazol-1-yl) -1H-pyrido [1,2-a ] pyrrolo [1,2-d ] pyrazine-5, 9-dione ((3S, 11aR) or (3R, 11aS)),

3- [ [3, 5-bis (trifluoromethyl) phenyl ] methyl ] -2,3,11,11 a-tetrahydro-8- (4-methyl-1H-imidazol-1-yl) -1H-pyrido [1,2-a ] pyrrolo [1,2-d ] pyrazine-5, 9-dione ((3S, 11aS) or (3R, 11aR)),

3- [ [3, 5-bis (trifluoromethyl) phenyl ] methyl ] -2,3,11,11 a-tetrahydro-8- (4-methyl-1H-imidazol-1-yl) -1H-pyrido [1,2-a ] pyrrolo [1,2-d ] pyrazine-5, 9-dione ((3R, 11aS) or (3S, 11aR)),

(3R, 11aS) -3- [3, 5-bis (trifluoromethyl) phenyl ] -2,3,11,11 a-tetrahydro-8- (4-methyl-1H-imidazol-1-yl) -1H-pyrido [1,2-a ] pyrrolo [1,2-d ] pyrazine-5, 9-dione,

(3S, 11aS) -3- [3, 5-bis (trifluoromethyl) phenyl ] -2,3,11,11 a-tetrahydro-8- (4-methyl-1H-imidazol-1-yl) -1H-pyrido [1,2-a ] pyrrolo [1,2-d ] pyrazine-5, 9-dione,

10- [ [3, 5-bis (trifluoromethyl) phenyl ] methyl ] -6, 6a, 7, 8, 9, 10-hexahydro-3- (4-methyl-1H-imidazol-1-yl) -bipyridino [1, 2-a: 1 ', 2' -d ] pyrazine-4, 12-diones,

10- [ [3, 5-bis (trifluoromethyl) phenyl ] methyl ] -6, 6a, 7, 8, 9, 10-hexahydro-3- (4-methyl-1H-imidazol-1-yl) -bipyridino [1, 2-a: 1 ', 2' -d ] pyrazine-4, 12-diones ((6aR, 10R) or (6aS, 10S)),

10- [ [3, 5-bis (trifluoromethyl) phenyl ] methyl ] -6, 6a, 7, 8, 9, 10-hexahydro-3- (4-methyl-1H-imidazol-1-yl) -bipyridino [1, 2-a: 1 ', 2' -d ] pyrazine-4, 12-diones ((6aS, 10R) or (6aR, 10S)),

10- [ [3, 5-bis (trifluoromethyl) phenyl ] methyl ] -6, 6a, 7, 8, 9, 10-hexahydro-3- (4-methyl-1H-imidazol-1-yl) -bipyridino [1, 2-a: 1 ', 2' -d ] pyrazine-4, 12-diones ((6aR, 10S) or (6aS, 10R)),

10- [ [3, 5-bis (trifluoromethyl) phenyl ] methyl ] -6, 6a, 7, 8, 9, 10-hexahydro-3- (4-methyl-1H-imidazol-1-yl) -bipyridino [1, 2-a: 1 ', 2' -d ] pyrazine-4, 12-dione ((6aS, 10S) or (6aR, 10R)),

the tautomers and the stereoisomeric forms thereof,

and pharmaceutically acceptable addition salts and solvates thereof.

In one embodiment, the compound of formula (I) is

Tautomers and stereoisomeric forms thereof,

and pharmaceutically acceptable addition salts and solvates thereof.

All possible combinations of the above-identified embodiments of interest are considered to be within the scope of the present invention.

Preparation of the Compounds

The invention also encompasses processes for the preparation of compounds of formula (I), intermediates and subgroups thereof. In the described reactions, it may be necessary to protect desired reactive functional groups, such as hydroxyl, amino, or carboxyl groups, in the final product to avoid their participation in undesired reactions. Conventional protecting Groups can be used according to standard practice (see, e.g., t.w. greens (Greene) and p.g.m. wutz (Wuts), "protecting Groups in organic chemistry" (John Wiley and Sons), 1991.

The compounds of formula (I) and subgroups thereof may be prepared by the sequential steps as described hereinafter and as described in the specific examples. They are generally prepared from starting materials that are commercially available or prepared by standard methods known to those of ordinary skill in the art. The compounds of the present invention may also be prepared using standard synthetic methods commonly used by those of ordinary skill in the art of organic chemistry.

The skilled artisan will recognize that in some reactions, microwave heating may be used instead of conventional heating to shorten the overall reaction time.

The general preparation of some representative examples is shown below.

Experimental procedure-scheme 1

Experimental procedure 1

Compounds of formula (I) wherein all variables are defined as described in the scope of the present invention, may be obtained by e.g. copper catalysed C-N coupling. Standard conditions include in a copper catalyst (such as CuI (cuprous iodide)), a base (such as Cs)₂CO₃(cesium carbonate)), a coupling partner such as, for example, 4-methylimidazole, and a ligand such as N, N' -dimethyl-1, 2-cyclohexanediamine, in a suitable solvent such as DMF (N, N-dimethylformamide). Degassing the reaction mixture with an inert gas (such as N2 or argon) and heating the reaction mixture to an elevated temperature (such as reflux temperature) may enhance reaction yield.

Alternatively, a compound of formula (I) (wherein R is³Limited to hydrogen) can be obtained by palladium-catalyzed C-N coupling. Typically, an intermediate of formula (II) is reacted in a base (such as K)₃PO₄Potassium phosphate), a source of palladium (such as Pd)₂(dba)₃(tris (dibenzylideneacetone) dipalladium (0)), a ligand such as 2-di-tert-butylphosphino-3, 4, 5, 6-tetramethyl-2 ', 4', 6 '-triisopropyl-1, 1' -diphenyl and the desired imidazole, in the presence of a solvent or a solvent mixture such as toluene/dioxane, stirring and heating. Premixing the catalyst and ligand, followed by heating prior to adding the remaining reagents, degassing and heating the solution, can increase the reaction yield.

Alternatively, a compound of formula (I) (wherein X is limited to CR)⁵And all other variables are defined as described in the scope of the present invention) can be obtained via a 5-step synthesis.

In a first step, intermediate (II) may be converted to intermediate (III) wherein PG is a mono-or di-valent nitrogen protecting group. For example, when PG ═ acetyl, the reaction can use known amidesCoupling methodology. For example, acetamide may be reacted with intermediate (II) in a base (such as K)₃PO₄) A source of palladium (such as Pd)₂(dba)₃) A ligand such as (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis [ diphenylphosphine](xanthene)) in a suitable solvent, such as anhydrous THF (tetrahydrofuran). In preparation with an inert gas (such as N)₂Or argon), anhydrous conditions, and the use of high temperatures (e.g., reflux temperature) can increase the reaction yield. In the second step, intermediate (III) can be converted to the free amine Intermediate (IV) by any deprotection method that is tolerated using other functions present in the molecule. For example, when PG ═ acetyl in intermediate (III), acid hydrolysis (using, for example, HCl (hydrochloric acid)) can be used in a suitable solvent such as MeOH (methanol). In a third step, the amino group in Intermediate (IV) may be acylated to give intermediate (V). For example, if R in the compound (V)³The formylation of Intermediate (IV), representing hydrogen, may be obtained by adding a formylating agent, e.g. a mixture of acetic anhydride and formic acid, to Intermediate (IV) dissolved in a suitable inert solvent, e.g. THF. Stirring the reaction under heating can increase the reaction yield. In the fourth step, the functions X and R can be carried out by methods known to those skilled in the art and according to the desired function⁴Converting intermediate (V) to cyclized precursor (VI). For example, if in compound (VII), X ═ CH and R⁴By reacting the intermediate (V) with a base (e.g. K)₂CO₃(potassium carbonate)) in a suitable solvent (e.g., DMF) is added to the desired α -haloketone (e.g., 1-bromo-2-butanone). If the halogen of the alpha-halo ketone is different from iodine, the reaction may be improved by an in situ Filkenstein reaction (performed by adding an iodide salt (e.g., KI) to the reaction mixture). Finally, intermediate (VII) can be converted to compound (I) by a classical imidazole synthesis. Diketone precursor (VII) can be cyclized to compound (I) in the presence of a nitrogen source, such as ammonium acetate, and an acid, such as AcOH. Heating the reaction to reflux temperature increases the reaction yield。

Experimental procedure-scheme 2

Experimental procedure 2

Intermediates of formula (II) wherein all variables are defined as described in the scope of the present invention can be obtained by direct bromination starting from intermediates of formula (VII). Different brominating agents can be used. For example, the reaction may be carried out by dissolving intermediate (VII) in a mixture of solvents such as DCM (dichloromethane)/AcOH (acetic acid) and adding bromine to the mixture, or by adding NBS (N-bromosuccinimide) to a solution of intermediate (VII) in a suitable solvent such as acetonitrile. The reaction mixture may be stirred under heat and an inert atmosphere.

Alternatively, intermediate (II) may be via an intermediate of formula (VIII) (wherein R is⁷Is C_1-4Alkyl) and an intermediate of formula (X). Typical conditions involve stirring the ester at elevated temperature in the presence of the desired amino alcohol of formula (X).

Alternatively, intermediate (II) can also be obtained by starting from intermediate (VIII) using a 2-step process. First, ester (VIII) can be saponified to give Intermediate (IX) (where M is a metal). The reaction can be carried out, for example, by adding a hydroxide, for example LiOH (lithium hydroxide), to a solution of the ester (VIII) in a suitable polar solvent or in a mixture of miscible solvents, one of which is highly polar, for example THF and water. Heating the reaction mixture may increase the reaction yield. In a second step, Intermediate (IX) may be reacted with an amino alcohol of formula (X) to provide intermediate (II). Typically, peptide coupling conditions may be applied, such as stirring the starting material dissolved in a suitable solvent (such as DMF) in the presence of a peptide coupling agent, such as HBTU (1- [ bis (dimethylamino) methylene ] -1H-benzotriazole-1-ium 3-oxide hexafluorophosphate). It will be appreciated by those of ordinary skill in the art that when a base such as DIPEA (N, N-diisopropylethylamine) is present in the mixture, the reaction provides the cyclized intermediate (II) directly. Heating the reaction mixture may increase the reaction yield.

Experimental procedure-scheme 2a

Experimental procedure 3

An intermediate of formula (II) (wherein L is-O-C)_1-6Alkanediyl-; and all variables are defined as described in the scope of the invention and are thus referred to as (II-a)) may be passed through an intermediate of formula (II-b) with a compound of formula R¹OH (wherein R¹Defined as described in the context of the present invention). The reaction mixture may be in a suitable base (such as K)₂CO₃) In a solvent such as DMF under heating and an inert atmosphere.

Experimental procedure 4

An intermediate of formula (II-b) (wherein X^aIs Cl, Br, I, OH, OMs (mesylate), OTs (tosilate); and all variables are defined as being within the scope of the invention) may be substituted by an intermediate of formula (VIII) (wherein R is⁷Is C_1-4Alkyl) and intermediates of formula (X-a) (wherein X is^bIs Cl, Br, I, OH, OMs, OTs). Typical conditions involve stirring the ester at elevated temperature in the presence of the desired amino alcohol of formula (X-a).

Alternatively, intermediate (II-b) can also be obtained by starting from intermediate (VIII) using a 2-step process. First, ester (VIII) can be saponified to give Intermediate (IX) (where M is a metal). The reaction can be carried out, for example, by adding a hydroxide, for example LiOH (lithium hydroxide), to a solution of the ester (VIII) in a suitable polar solvent or in a mixture of miscible solvents, one of which is highly polar, for example THF and water. Heating the reaction mixture may increase the reaction yield. In a second step, Intermediate (IX) may be reacted with an amino alcohol of formula (X-a) to provide intermediate (II-b). Typically, peptide coupling conditions may be applied, such as stirring the starting material dissolved in a suitable solvent (such as DMF) in the presence of a peptide coupling agent, such as HBTU (1- [ bis (dimethylamino) methylene ] -1H-benzotriazole-1-ium 3-oxide hexafluorophosphate). It will be appreciated by those of ordinary skill in the art that when a base such as DIPEA (N, N-diisopropylethylamine) is present in the mixture, the reaction provides the cyclized intermediate (II-b) directly. Heating the reaction mixture may increase the reaction yield.

An intermediate of formula (X-a) (wherein

X^aIs Cl, Br, I, OH, OMs, OTs;

X^bis Cl, Br, I, OH, OMs, OTs;

and all variables are defined as being within the scope of the invention) are commercially available or can be prepared by methods known to those of ordinary skill in the art starting from commercially available compounds.

Experimental procedure-scheme 3

Experimental procedure 5

An intermediate of formula (VIII) (wherein

R⁷Is C_1-4An alkyl group;

all other variables are defined as described in the scope of the present invention) are commercially available or can be obtained via acidic hydrolysis of intermediate (XIII). The reaction may be carried out, for example, by stirring the starting materials in the presence of an acid (e.g., trifluoroacetic anhydride) in a suitable solvent (e.g., DMF). The reaction mixture may be stirred under heat and an inert atmosphere.

Experimental procedure 6

An intermediate of formula (XIII) (wherein

R⁷Is C_1-4An alkyl group;

and all variables are defined as being within the scope of the present invention) can be obtained by N-oxidative deprotection of intermediate (XII) by methods known to those of ordinary skill in the art. The reaction may be carried out, for example, in the presence of a peroxide, such as urea hydrogen peroxide, and an activator, such as trifluoroacetic anhydride, in a suitable solvent, such as MeCN (acetonitrile).

Experimental procedure 7

An intermediate of formula (XII) (wherein

R⁷Is C_1-4An alkyl group;

and all variables are defined as being within the scope of the present invention) can be obtained by esterification of the commercially available intermediate (XI) by methods known to those of ordinary skill in the art. The reaction may be carried out, for example, in the presence of a chlorinating agent, such as thionyl chloride, and an alcohol, such as MeOH, in a suitable solvent, such as MeOH. Precooling of the solution prior to addition of the chlorinating agent can increase the reaction yield.

Experimental procedure-scheme 4

Experimental procedure 8

An intermediate of formula (X-b-PG) (wherein L is limited to L)^a

L^aIs attached to location a;

L^ais a covalent bond or-C_1-6Alkanediyl-;

PG is a protecting group known to those of ordinary skill in the art;

and all other variables are defined as being as described in the scope of the present invention) are obtainable via protection of the alcohol function of (X-b) of the intermediate. The protection may be, for example, silylation, which may be carried out in the presence of a suitable solvent, e.g., DCM, an additive, such as imidazole, and a silylating agent, such as TBSCl (tert-butyldimethylchlorosilane) or TMSCl (trimethylchlorosilane), following standard conditions known to those of ordinary skill in the art.

Experimental procedure 9

An intermediate of formula (X-b), wherein all other variables are defined as described in the scope of the present invention, can be reduced via the ester function of intermediate (XXI-b), for example by using NaBH₄(sodium borohydride) or LiAlH₄(lithium aluminum hydride) in a suitable solvent (such as MeOH or Et)₂O (diethyl ether)). Precooling the reaction mixture before adding the reducing agent can increase the reaction yield.

Experimental procedure 10

An intermediate of formula (XXI-b) (wherein

R⁸Is C_1-4An alkyl group;

and all other variables are defined as described in the scope of the inventionCan be reduced via the imino function of the intermediate (XX-b), for example by using NaBH₃CN (sodium cyanoborohydride) is obtained in the presence of a suitable solvent, such as 2-propanol. Precooling the reaction mixture before adding the reducing agent can increase the reaction yield.

Experimental procedure 11

An intermediate of formula (XX-b) (wherein

R⁸Is C_1-4An alkyl group;

and all variables are defined as being within the scope of the invention) can be obtained by deprotection followed by in situ cyclization by methods known to those of ordinary skill in the art. For example, when PG ═ Boc (tert-butoxycarbonyl), deprotection can be achieved by treating intermediate (XIX-b) dissolved in a suitable solvent such as DCM with a strong acid such as TFA (trifluoroacetic acid).

Experimental procedure 12

An intermediate of formula (XVIII) (wherein

X^cIs chlorine or bromine;

and all variables are defined as being within the scope of the invention) are commercially available or obtained by preparation of grignard reagents and intermediates of formula (XVII) following methods known to those of ordinary skill in the art. Typical conditions will be for example magnesium in a suitable inert solvent (such as Et)₂O) intermediate (XVII). The reaction mixture may be stirred under heat and an inert atmosphere.

Experimental procedure 13

An intermediate of formula (XIX-b) (wherein

R⁸Is C_1-4Alkyl and PG is a protecting group known to those of ordinary skill in the art;

and all other variables are defined as being within the scope of the invention) may be obtained by reacting an intermediate of formula (XVI-b) with an intermediate of formula (XVIII). Precooling of the solution prior to addition of the grignard reagent can increase the reaction yield.

Experimental procedure 14

An intermediate of formula (XVI-b) (wherein

and all other variables are defined as being described in the scope of the present invention) are obtainable via protection of the amide function of intermediate (XV-b). The protection may be, for example, Boc protection, which may be performed in a suitable solvent (such as MeCN), an additive (e.g. DMAP (dimethylaminopyridine)) and a protecting agent (such as (Boc))₂O (di-tert-butyl carbonate)) in the presence of oxygen, following standard conditions known to those of ordinary skill in the art.

Experimental procedure 15

An intermediate of formula (XV-b) (wherein

R⁸Is C_1-4An alkyl group;

and all variables are defined as being within the scope of the present invention) can be obtained by esterification of the commercially available intermediate (XIV-b) by methods known to those of ordinary skill in the art. The reaction may be carried out, for example, in the presence of a chlorinating agent (such as thionyl chloride) and an alcohol (such as EtOH) in a suitable solvent (such as EtOH). Precooling of the solution prior to addition of the chlorinating agent can increase the reaction yield.

Experimental procedure-scheme 4a

Alternatively, an intermediate of formula (X) (wherein

L is attached at position a or b and is limited to one covalent bond;

y is- (CH)₂)_n-, where n is 2;

PG is a protecting group and is therefore called intermediate (X-c-PG)), and can be obtained starting from intermediate (X-c) via protection of the alcohol function of intermediate (X-c). For example, the protection may be silylation, which may be carried out in the presence of a suitable solvent, e.g., DCM, an additive (such as imidazole) and a silylating agent (such as TBSCl or TMSCl), following standard conditions known to those of ordinary skill in the art.

Intermediates of formula (X-c), wherein all other variables are defined as described in the scope of the present invention, can be reduced by ester function of intermediates (XXI-c), for example by using NaBH₄In the presence of a suitable solvent, such as MeOH. Precooling the reaction mixture before adding the reducing agent can increase the reaction yield.

Intermediates of formula (XXI-c) (wherein

R⁹Is C_1-4An alkyl group;

and all variables are defined as being within the scope of the invention) can be obtained by hydrogenation of intermediate (XXIII-c), for example by stirring a solution of intermediate (XXIII-c) in a suitable solvent, such as AcOH (acetic acid), and in a hydrogenation catalyst, such as PtO (acetic acid)₂(platinum (IV) oxide))) in the presence of hydrogen.

Intermediates of formula (XXIII-c) (wherein

R⁹Is C_1-4An alkyl group;

and all variables are defined as being within the scope of the invention) may be obtained by, for example, palladium catalyzed C-C coupling. Standard conditions involve the commercially available intermediate (XXII-c) (where X^dIs Br, Cl or I) over a palladium catalyst (such as tetrakis (triphenylphosphine) palladium (0)), a suitable base (such as K)₂CO₃) And coupling partners such as, for example, 3, 5-bis (trifluoromethyl) phenylboronic acid, in the presence of a solvent such as DMF. With an inert gas (such as N)₂Or argon) degassing the reaction mixture, and heating the reaction mixture to an elevated temperature (such as reflux temperature) may enhance the reaction outcome.

Optionally, an intermediate of formula (XXII-c) may be substituted at γ or with hydroxy. The hydroxyl group can be oxidized in an intermediate of formula (XXI-c) to obtain the corresponding ketone, which can then be converted by Grignard reaction to the corresponding intermediate in gamma or position in one CH₂Containing hydroxy and C_1-4An alkyl moiety.

Experimental procedure-scheme 5

Experimental procedure 14

Intermediates of formula (VII) (wherein all variables are defined as described in the scope of the present invention) can be obtained via intramolecular cyclization, e.g. by applying the conditions of the Mitsunobu reaction to intermediate (XXVIII). The reaction may be carried out by treating a solution of intermediate (XXVIII) in a suitable inert and anhydrous solvent, such as THF, with an azodicarboxylate species, such as DIAD (diisopropyl azodicarboxylate), in the presence of a phosphine, such as triphenylphosphine, under an inert atmosphere. A pre-cooling of the solution may be used.

Experiment ofProcedure 15

An intermediate of formula (XXVIII) can be obtained via debenzylation of a compound of formula (XXVII) using standard methods compatible with the presence of a protecting agent. In the case of intermediate (XXVII), for example, debenzylation may be accomplished by hydrogenation (by stirring a solution of intermediate (XXVII) in a suitable solvent, such as MeOH, and in the presence of a hydrogenation catalyst, such as Pd/C (palladium on carbon), under a hydrogen atmosphere).

Experimental procedure 16

An intermediate of formula (XXVII) may be obtained by deprotection of intermediate (XXVI) by methods known to those of ordinary skill in the art. In the case of a silyl protecting group, for example, the standard method would be to treat intermediate (XXVI) dissolved in a suitable solvent (e.g., THF) with a fluorine source (e.g., TBAF (tetrabutylammonium fluoride)).

Experimental procedure 17

An intermediate of formula (XXVI) can be obtained starting from intermediate (X-PG) and acid (XXV) using, for example, standard peptide coupling conditions. Typically, the peptide coupling conditions may be applied, for example stirring the starting material, dissolving in a suitable solvent (such as DMF), in the presence of a peptide coupling agent (such as HBTU) and in the presence of a base (such as DIPEA). Cooling the reaction mixture may increase the reaction yield.

Experimental procedure 18

An intermediate of formula (X-PG) can be obtained via protection of the alcohol function of intermediate (X). The protection may be, for example, silylation, which may be carried out in the presence of a suitable solvent, e.g., DCM, an additive (such as imidazole) and a silylating agent (such as TBSCl or TMSCl), following standard conditions known to those of ordinary skill in the art.

Experimental procedure 19

An intermediate of formula (XXV) may be prepared by intermediate (XXIV) (wherein X is^eAre Cl, Br and I, which are compatible with the presence of protecting groups in the following steps). The protection may be, for example, benzylation, which may be carried out in the presence of a suitable solvent, such as THF, a suitable base, such as NaH (sodium hydride), and benzyl alcohol, following standard conditions known to those of ordinary skill in the art.

Experimental procedure-scheme 6

Experimental procedure 20

Alternatively, a 4-step process starting from intermediate (X) and intermediate (XXV) may be used. First, typically, the peptide coupling conditions may be applied, for example stirring the starting material, dissolving in a suitable solvent (such as DMF), in the presence of a peptide coupling agent (such as HBTU) and in the presence of a base (such as DIPEA). Cooling the reaction mixture may increase the reaction yield. The free hydroxyl function in intermediate (XXIX) can then be converted into a suitable leaving group. For example, intermediate (XXX), wherein LG ═ chloro and wherein Bn ═ benzyl, can be obtained under mild conditions by dissolving intermediate (XXIX) in a suitable solvent such as DCM and treating it with a chlorinating agent such as thionyl chloride. Precooling of the solution prior to addition of the chlorinating agent can increase the reaction yield. Intermediate (XXX) may then be subjected to debenzylation to give intermediate (XXXI) using standard methods compatible with the presence of a leaving group. For example, debenzylation may be achieved by the use of a Lewis acid (such as BBr)₃(boron tribromide)) is achieved by treating the intermediate dissolved in a suitable and inert solvent, such as DCM. Precooling the reaction mixture before adding the lewis acid can increase the reaction yield. Finally, intermediate (XXXI) can be processed to intermediate (VII) by using standard substitution conditions. For example, fromStarting from intermediate (XXXI) (where LG ═ chloro), ring closure can be achieved by treating the substrate dissolved in a suitable solvent such as DMF with a base such as NaH (sodium hydride). Precooling the reaction and dilution levels high enough to avoid intermolecular interactions can increase the reaction yield.

The starting materials may be commercially available or may be prepared by one of ordinary skill in the art.

Any one or more of the following additional steps can be performed in any order, as necessary or desired:

the compounds of formula (I) and any subgroups thereof may be converted to further compounds of formula (I) and any subgroups thereof using procedures known in the art.

It will be appreciated by those of ordinary skill in the art that in the processes described above, it may be desirable to block the functional groups of the intermediate compound by protecting groups. In case the functional group of the intermediate compound is blocked by a protecting group, it may be deprotected after one reaction step.

In all of these preparations, the reaction products can be isolated from the reaction medium and, if desired, further purified according to methods generally known in the art, such as, for example, extraction, crystallization, trituration, and chromatography. In particular, stereoisomers may be used using chiral stationary phases such as, for exampleAD (amylose 3, 5-dimethylphenylcarbamate) orAS (both available from cellosolve chemical Industries, Ltd, japan) was chromatographically separated, or separated by Supercritical Fluid Chromatography (SFC).

The chirally pure forms of the compounds of formula (I) form a preferred group of compounds. The chirally pure forms of the intermediates and their salt forms are therefore particularly useful in the preparation of chirally pure compounds of formula (I). Enantiomeric mixtures of intermediates are also useful in the preparation of compounds of formula (I) having the corresponding configuration.

Pharmacology of

The compounds of the invention have been found to modulate gamma-secretase activity. Thus, the compounds according to the present invention and pharmaceutically acceptable compositions thereof are useful in the treatment or prevention of AD, TBI, dementia pugilistica, MCI, senility, dementia with lewy bodies, cerebral amyloid angiopathy, multi-infarct dementia, down's syndrome, dementia associated with parkinson's disease and dementia associated with beta-amyloid; AD is preferred.

The compounds according to the invention and pharmaceutically acceptable compositions thereof may be used for the treatment or prevention of a disease or condition selected from the group consisting of: AD. TBI, dementia pugilistica, MCI, senility, dementia with Lewy bodies, cerebral amyloid angiopathy, multi-infarct dementia, Down's syndrome, dementia associated with Parkinson's disease and dementia associated with beta-amyloid.

The skilled artisan will be familiar with alternative glossaries, disease taxonomies, and classification systems for diseases or conditions referred to herein. For example, the American psychiatric Association's handbook for diagnosis and statistics of mental disorders, fifth edition (DSM-5)^TM) Terms are used such as neurocognitive disorder (NCD) (both severe and mild), in particular, neurocognitive disorder caused by alzheimer's disease, neurocognitive disorder caused by Traumatic Brain Injury (TBI), neurocognitive disorder caused by lewy body disease, neurocognitive disorder caused by parkinson's disease or neurocognitive disorder caused by vascular NCD such as vascular NCD manifested as multi-infarct. The skilled person may use such terms as alternative nomenclature for some of the diseases or conditions mentioned herein.

As used herein, the term "modulation of γ -secretase activity" refers to the effect of treating APP by a γ -secretase-complex. Preferably, this refers to a situation where the overall rate of APP processing remains substantially the same without administration of the compound, but where the relative amount of processed product is altered, more preferably in such a way that the amount of Α β 42-peptide produced is reduced. For example, different A.beta.species may be produced (e.g., A.beta.38 of shorter amino acid sequence or other species of A.beta.peptide in place of A.beta.42) or the relative amounts of the products may be different (e.g., the ratio of A.beta.40 to A.beta.42 is altered, preferably increased).

It has previously been shown that the gamma-secretase complex is also involved in Notch-protein processing. Notch is a signaling protein that plays a critical role in developmental processes (as reviewed, for example, in schweisgutt (Schweisguth F) (2004) contemporary biology 14, R129). Regarding the use of gamma-secretase modulators in therapy, it appears to be particularly advantageous for Notch-processing activities that do not interfere with gamma-secretase activity, in order to avoid the presumed undesirable side effects. However, since inhibitors of γ -secretase show side effects with concomitant inhibition of Notch processing, γ -secretase modulators may have the ability to selectively reduce the production of the highly aggregatable and neurotoxic form of a β (i.e., a β 42), without reducing the production of the smaller, less aggregatable form of a β (i.e., a β 38) and without concomitant inhibition of Notch processing. Therefore, compounds that do not exhibit an effect on the Notch-processing activity of the γ -secretase complex are preferable.

As used herein, the term "treatment" is intended to refer to all processes in which there may be a slowing, interrupting, arresting or stopping of the progression of a disease or the relief of symptoms, but does not necessarily indicate the total elimination of all symptoms.

The term "subject" as used herein refers to an animal, preferably a mammal, most preferably a human, who is or has been the subject of treatment, observation or experiment.

The present invention relates to compounds according to general formula (I), and pharmaceutically acceptable acid or base addition salts and solvates thereof, for use as a medicament.

The invention also relates to compounds according to general formula (I), and pharmaceutically acceptable acid or base addition salts and solvates thereof, for use in modulating gamma-secretase activity.

The invention also relates to compounds according to general formula (I), and pharmaceutically acceptable acid or base addition salts and solvates thereof, for use in the treatment or prevention of a disease or condition selected from the group consisting of: AD. TBI, dementia pugilistica, MCI, senility, dementia with lewy bodies, cerebral amyloid angiopathy, multi-infarct dementia, down's syndrome, dementia associated with parkinson's disease and dementia associated with beta-amyloid.

The invention also relates to compounds according to general formula (I), and the pharmaceutically acceptable acid or base addition salts and solvates thereof, for use in the treatment or prevention of a disease or condition selected from: a neurocognitive disorder due to Alzheimer's disease, a neurocognitive disorder due to traumatic brain injury, a neurocognitive disorder due to Lewy body disease, a neurocognitive disorder due to Parkinson's disease, or a vascular neurocognitive disorder.

In one embodiment, the disease or disorder is preferably AD.

The invention also relates to compounds according to general formula (I), and the pharmaceutically acceptable acid or base addition salts and solvates thereof, for use in the treatment of said diseases.

The invention also relates to compounds according to general formula (I), and the pharmaceutically acceptable acid or base addition salts and solvates thereof, for use in the treatment or prevention of said diseases.

The invention also relates to compounds according to general formula (I), and pharmaceutically acceptable acid or base addition salts and solvates thereof, for use in the treatment or prevention, especially treatment, of a gamma-secretion mediated disease or condition.

The invention also relates to the use of compounds according to general formula (I), and the pharmaceutically acceptable acid or base addition salts and solvates thereof, for the manufacture of a medicament.

The invention also relates to the use of a compound according to general formula (I), and pharmaceutically acceptable acid or base addition salts and solvates thereof, for the manufacture of a medicament for the treatment or prevention of any of the above mentioned disease conditions.

The invention also relates to the use of a compound according to general formula (I), and pharmaceutically acceptable acid or base addition salts and solvates thereof, for the manufacture of a medicament for the treatment of any of the above mentioned disease conditions.

In the present invention, particular preference is given to compounds of formula (I), and pharmaceutically acceptable acid or base addition salts and solvates thereof, or any subgroup thereof, which have an IC of inhibition of production of a β 42-peptide of less than 1000nM, preferably less than 100nM, more preferably less than 50nM, even more preferably less than 20nM, as determined by a suitable assay, such as the one used in the examples below₅₀The value is obtained.

The compounds of formula (I), and the pharmaceutically acceptable acid or base addition salts and solvates thereof, may be administered to a mammal, preferably a human, for the treatment or prevention of any of the diseases mentioned hereinbefore.

In view of the utility of the compounds of formula (I), and the pharmaceutically acceptable acid or base addition salts and solvates thereof, there is provided a method of treating a subject, particularly a warm-blooded animal, including a human being, suffering from any one of the diseases mentioned hereinbefore, or a method of preventing a subject, particularly a warm-blooded animal, including a human being, suffering from any one of the diseases mentioned hereinbefore.

Said method comprising administering, i.e. systemically or locally, preferably orally, to a subject, in particular a warm-blooded animal, including a human, an effective amount of a compound of formula (I), and pharmaceutically acceptable acid or base addition salts and solvates thereof.

Accordingly, the present invention also relates to a method of treating or preventing a disease or condition selected from: alzheimer's disease, traumatic brain injury, mild cognitive impairment, senility, dementia with lewy bodies, cerebral amyloid angiopathy, multi-infarct dementia, dementia pugilistica, down's syndrome, dementia associated with parkinson's disease and dementia associated with beta-amyloid, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition according to the invention.

The present invention also relates to a method of treating or preventing a disease or condition selected from: neurocognitive disorders due to alzheimer's disease, neurocognitive disorders due to traumatic brain injury, neurocognitive disorders due to lewy body disease, neurocognitive disorders due to parkinson's disease or vascular neurocognitive disorders, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition according to the invention.

The invention also relates to the use of compounds of formula (I), and the pharmaceutically acceptable acid or base addition salts and solvates thereof, for modulating gamma-secretase activity resulting in a reduction in the relative amount of a β 42-peptide produced.

An advantage of the compounds or a part of the compounds of the invention is that they enhance CNS-penetration.

In the treatment of such diseases, the ordinarily skilled artisan can determine the effective daily amount of treatment from the test results provided below. An effective daily amount for treatment will be from about 0.005mg/kg to 50mg/kg, specifically 0.01mg/kg to 50mg/kg body weight, more specifically 0.01mg/kg to 25mg/kg body weight, preferably from about 0.01mg/kg to about 15mg/kg, more preferably from about 0.01mg/kg to about 10mg/kg, even more preferably from about 0.01mg/kg to about 1mg/kg, most preferably from about 0.05mg/kg to about 1mg/kg body weight. The amount of a compound of the invention (also referred to herein as an active ingredient) required to achieve a therapeutically effective amount will, of course, vary from one case to another, e.g., the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated.

The method of treatment may also include administering the active ingredient on a regimen of between once and four intakes per day. In these methods of treatment, the compounds according to the invention are preferably formulated prior to administration. Suitable pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients, as described below.

The compounds of the present invention, which may be suitable for the treatment or prevention of alzheimer's disease or symptoms thereof, may be administered alone or in combination with one or more additional therapeutic agents. The combination therapy comprises: the administration of a single pharmaceutical dosage formulation comprising a compound of formula (I), one of its pharmaceutically acceptable acid or base addition salts, or solvates, and one or more additional therapeutic agents, together with the administration of a compound of formula (I), one of its pharmaceutically acceptable acid or base addition salts, or solvates, and each additional therapeutic agent present in its own separate pharmaceutical dosage formulation. For example, a compound of formula (I) or a pharmaceutically acceptable acid or base addition salt or solvate thereof and one therapeutic agent may be administered to a patient together in a single oral dosage composition, such as a tablet or capsule, or each agent may be administered in separate oral dosage formulations.

While it is possible for the active ingredient to be administered alone, it is preferred that it be presented in the form of a pharmaceutical composition.

Accordingly, the present invention further provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound according to formula (I), a pharmaceutically acceptable acid or base addition salt or solvate thereof.

The carrier or diluent must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

For ease of administration, the subject compounds may be formulated in a variety of pharmaceutical forms for administration purposes. The compounds according to the invention, in particular the compounds according to formula (I), and the pharmaceutically acceptable acid or base addition salts and solvates thereof, or any subgroup or combination thereof, may be formulated in different pharmaceutical forms for administration purposes. All compositions which are generally intended for systemic administration can be cited as suitable compositions.

To prepare the pharmaceutical compositions of the present invention, an effective amount of the particular compound as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. It is desirable that these pharmaceutical compositions be in unit dosage forms particularly suitable for administration via oral, rectal, transdermal, parenteral injection or inhalation. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, and the like, in the case of oral liquid preparations (such as suspensions, syrups, elixirs, emulsions, and solutions); or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because they facilitate administration, tablets and capsules represent the most advantageous oral dosage forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will typically comprise sterile water, at least in large part, but may also comprise other ingredients, for example to aid solubility. Injectable solutions, for example, may be prepared in which the carrier comprises a physiological saline solution, a glucose solution, or a mixture of physiological saline and glucose solution. Injectable solutions, for example, may be prepared in which the carrier comprises a physiological saline solution, a glucose solution, or a mixture of physiological saline and glucose solution. Injectable solutions comprising a compound of formula (I), one of its pharmaceutically acceptable acid or base addition salts or solvates, may be formulated in oils to prolong the effect. Suitable oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerides of long-chain fatty acids and mixtures of these with other oils. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. In compositions suitable for transdermal administration, the carrier may optionally include a penetration enhancer and/or suitable wetting agent, optionally in combination with small proportions of suitable additives of any nature which do not introduce significant deleterious effects on the skin. The additives may facilitate administration to the skin and/or may aid in the preparation of the desired composition. These compositions can be administered in different ways, e.g., as a transdermal patch, as a spot-on, as an ointment. Acid or base addition salts of compounds of formula (I) are more suitable for preparing aqueous compositions because of their increased solubility relative to the corresponding base or acid form.

It is particularly advantageous to formulate the above pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form, as used herein, refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets (powder packets), wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.

Since the compounds according to the invention are effective orally administrable compounds, pharmaceutical compositions comprising said compounds for oral administration are particularly advantageous.

In order to increase the solubility and/or stability of the compounds of formula (I), their pharmaceutically acceptable acid or base addition salts and solvates in the pharmaceutical composition, it is advantageous to employ alpha-, beta-or gamma-cyclodextrins or derivatives thereof, in particular hydroxyalkyl-substituted cyclodextrins, such as 2 hydroxypropyl-beta-cyclodextrin or sulfobutyl-beta-cyclodextrin. Auxiliary solvents, such as alcohols, may also improve the solubility and/or stability of the compounds according to the invention in pharmaceutical compositions.

Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% by weight, more preferably from 0.1 to 70% by weight, even more preferably from 0.1 to 50% by weight of the compound of formula (I), a pharmaceutically acceptable acid or base addition salt or solvate thereof, and from 1 to 99.95% by weight, more preferably from 30 to 99.9% by weight, even more preferably from 50 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

The following examples illustrate the invention. If no specific stereochemistry is indicated for the stereocenter of a compound, this means that a mixture of the compounds in the R and S enantiomers is obtained.

Examples of the invention

Hereinafter, the term "AcOH" means acetic acid; "aq." means aqueous; "Bn" means benzyl; "DCM" means dichloromethane; "DIPE" means diisopropyl ether; "DIPEA" means N, N-diisopropylethylamine; "DMAP" means 4- (dimethylamino) pyridine; "DMF" means N, N-dimethylformamide; "DMSO" means dimethylsulfoxide; "Et₃N "means triethylamine; "EtOH" means ethanol; et (Et)₂O means diethyl ether; "EtOAc" means ethyl acetate; "h" means hours; "HBTU" means 1- [ bis (dimethylamino) methylene]-1H-benzotriazol-1-ium 3-oxide hexafluorophosphate; "HPLC" means high performance liquid chromatography; "LCMS" means liquid chromatography/mass spectrometry; "MeCN" means acetonitrile; "MeOH" means methanol; meaning "minThe time is minutes; "m.p." means melting point; "Pd (PPh)₃)₄"means tetrakis (triphenylphosphine) palladium; ' Pd₂(dba)₃"means tris [ mu- [ (1, 2-. eta.: 4, 5-. eta.) - (1E, 4E) -1, 5-diphenyl-1, 4-pentadien-3-one]]) Dipalladium; "Pd (OAc)₂"means palladium diacetate (2 +); "r.m." means the reaction mixture; "RP" means inverse; "r.t" means room temperature; "sat." means saturated; "sol." means a solution; "TBDMS" means t-butyldimethylsilyl; "TFA" means trifluoroacetic acid and "THF" means tetrahydrofuran.

A. Preparation of intermediates

Example A1

a) Preparation of intermediate 1

A solution of DL-pyroglutamic acid (90g, 697mmol) and 4-methylbenzenesulfonic acid hydrate (13.26g, 69.7mmol) in EtOH (110ml) was stirred at 65 ℃ for 72 h. The reaction mixture was cooled to room temperature and evaporated in vacuo. Addition of Et₂O (11) and the mixture is taken up with saturated aqueous NaHCO₃The solution (300ml) was washed. The separated organic phase was dried (MgSO)₄) And (4) filtering. The aqueous phase was extracted with DCM (3 times). The separated organic phase was dried (MgSO)₄) Filtered and the organic layers were combined and evaporated in vacuo. Yield: 80g of intermediate 1 (73%).

b) Preparation of intermediate 2

Thionyl chloride (5.45ml, 74.76mmol) was added dropwise to D-glutamic acid (5g, 34mmol) in EtOH (25ml) over 1h at 5 ℃. After the addition was complete, the reaction mixture was stirred at room temperature for 1h and then heated at 80 ℃ for 1 h. The reaction mixture was evaporated in vacuo. The residue was taken up in EtOH and neutralized to pH 7 with 1% KOH solution in EtOH. The solid was filtered and the filtrate was concentrated to dryness. The residue was heated at 90 ℃ for 1h and at 150 ℃ under high vacuum (1 mbar (mmbar)) for 1 h. The residue was washed with heptane and dried in vacuo. The crude material was used as such in the next reaction step. Yield: 3.92g of intermediate 2 (73%).

Example A2

a) Preparation of intermediate 3

A mixture of intermediate 1(4.3g, 27.36mmol), di-tert-butyldicarbonate (7.17g, 32.83mmol), DMAP (0.17g, 1.37mmol) in MeCN (43.6ml) was stirred at room temperature under nitrogen for 2 h. The solvent was evaporated in vacuo and the residue was dissolved in Et₂O (200 ml). The organic phase was cooled to 0 ℃ and washed with HCl1N solution (15ml) and then brine (20 ml). The separated organic phase was dried (MgSO)₄) Filtered and the organic layers were combined and evaporated in vacuo. The crude product was purified by flash column chromatography (eluent: EtOAc/DCM from 5/95 to 10/90). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 6.6g of intermediate 3 (94%).

b) Preparation of intermediate 4

Starting from methyl 6-oxo-piperidine-2-carboxylate, intermediate 4 was prepared by using a similar reaction scheme as described in example a2. a).

c) Intermediate (II)Preparation of body 5

Starting from intermediate 2, intermediate 5 was prepared by using an analogous reaction scheme as described in example a2. a).

Example A3

Preparation of intermediate 6

Magnesium (396mg, 16.28mmol) in Et₂Stirring was carried out in O (5 ml). Then a few drops of 3, 5-bis (trifluoromethyl) benzyl bromide were added. The reaction mixture was warmed and the reaction was initiated. Then add additional Et₂O (5ml) and added dropwise to Et under spontaneous reflux₂3, 5-bis (trifluoromethyl) benzyl bromide (5g, 16.28mmol) in O (20 ml). The reaction mixture was refluxed for 3h and cooled to room temperature. The crude product was used as intermediate 6 in the next step without further purification.

Example A4

a) Preparation of intermediate 7

Intermediate 3(28g, 108.8mmol) in Et₂O (704ml) was stirred at-50 ℃ under nitrogen. Intermediate 6(41.47g, 125.1mmol) was then added dropwise, maintaining the temperature between-40 ℃ and-50 ℃. The reaction mixture was stirred at-40 ℃ for 1h, warmed to 10 ℃ and stirred at 0 ℃ to 10 ℃ for 1 h. The reaction mixture was then cooled to-10 ℃. Dropwise addition of saturated aqueous NH₄Cl solution (60ml), then water was added to dissolveAll salts are decomposed. The aqueous phase is washed with Et₂Wash with O (2 × 100 ml). The separated organic phase was dried (MgSO)₄) Filtered and the organic layers were combined and evaporated in vacuo. The crude product was purified by flash column chromatography (eluent: EtOAc/DCM from 0/100 to 2/98). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 31g of intermediate 7 (57%).

b) Preparation of intermediate 8

Starting from intermediate 4 and intermediate 6, intermediate 8 was prepared by using a similar reaction scheme as described in example a4. a).

b) Preparation of intermediate 9

Starting from intermediate 5 and intermediate 6, intermediate 9 was prepared by using an analogous reaction scheme as described in example a4. a).

c) Preparation of intermediate 10

Starting from intermediate 5 and 3, 4-dichlorophenyl magnesium bromide, intermediate 10 was prepared by using a similar reaction scheme as described in example a4. a).

Example A5

a) Preparation of intermediate 11

Intermediate 7(28g, 57.68mmol) was stirred in DCM (850mL) at 5 ℃. TFA (64ml, 836mmol) was added at 5 ℃. The reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was then cooled and TFA (24ml, 313mmol) was added. The reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was then cooled and TFA (24ml, 313mmol) was added. The reaction mixture was cooled to 5 ℃ and Et was added₃N (240ml, 1.7 mol). The reaction mixture was stirred at room temperature for 10min and water was added. The aqueous phase was extracted with DCM (twice). The separated organic phase was dried (MgSO)₄) Filtered and the organic layers were combined and evaporated in vacuo. The crude product was purified by flash column chromatography (eluent: EtOAc/DCM 5/95). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 20g of intermediate 11 (71%).

b) Preparation of intermediate 12

Starting from intermediate 8, intermediate 12 was prepared by using an analogous reaction scheme as described in example a5. a).

c) Preparation of intermediate 13

Starting from intermediate 9, intermediate 13 was prepared by using an analogous reaction scheme as described in example a5. a).

c) Preparation of intermediate 14

Starting from intermediate 10, intermediate 14 was prepared by using an analogous reaction scheme as described in example a5. a).

Example A6

a) Preparation of intermediate 15

HCl (37% in water) (40.93ml, 490.1mmol) was added to intermediate 11(15g, 40.8mmol) in 2-propanol (470ml) at 5 ℃. Sodium cyanoborohydride (12.83g, 204.2mmol) was then added in portions at 5 ℃. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured in portions into saturated aqueous NaHCO at a cooled t < 10 deg.C₃In solution (700 ml). The aqueous phase was washed with EtOAc (twice). The separated organic phase was dried (MgSO)₄) Filtered and the organic layers were combined and evaporated in vacuo. The crude product was purified by flash column chromatography (eluent: EtOAc/DCM 10/90). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 8g of intermediate 15 (53%).

b) Preparation of intermediate 16

Starting from intermediate 12, intermediate 16 was prepared by using an analogous reaction scheme as described in example a 6.a).

c) Preparation of intermediate 17

Starting from intermediate 13, intermediate 17 was prepared by using an analogous reaction scheme as described in example a 6.a).

d) Preparation of intermediate 18

Starting from intermediate 14, intermediate 18 was prepared by using an analogous reaction scheme as described in example a 6.a).

Example A7

a) Preparation of intermediate 19

Sodium borohydride (1.84g, 3.25mmol) was added in small portions to a stirred solution of intermediate 15(1.2g, 3.25mmol) in MeOH (23ml) cooled with an ice/EtOH bath under nitrogen. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was washed with DCM (50ml) and saturated aqueous NH₄The Cl solution (20mL) was diluted and stirred for 30 min. The aqueous layer was extracted with DCM (3 × 50 ml). The separated organic phase was dried (MgSO)₄) Filtered and the organic layers were combined and evaporated in vacuo. By flash column chromatography (eluent: MeOH (NH)₃) /DCM from 2.5/97.5 to 5/95). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 770mg of intermediate 19 (72%).

b) Preparation of intermediate 20

Starting from intermediate 16, intermediate 20 was prepared by using an analogous reaction scheme as described in example a 7.a).

Example A8

a) Preparation of intermediate 21

Lithium aluminium hydride (0.55g, 14.44mmol) was added in portions to intermediate 17(5.13g, 14.44mmol) in Et under nitrogen₂Cooled solution in O (140 ml). The reaction mixture was stirred at 0 ℃ for 2 h. The reaction mixture was quenched with water and Et₂And (4) extracting. The separated organic phase was dried (MgSO)₄) Filtered and the organic layers were combined and evaporated in vacuo. Yield: 4.5g of intermediate 21 (99%).

b) Preparation of intermediate 22

Starting from intermediate 18, intermediate 22 was prepared by using an analogous reaction scheme as described in example a 8.a).

Example A9

Preparation of intermediate 23

To a suspension of intermediate 21(4.5g, 14.37mmol), imidazole (2.93g, 43.1mmol) in DCM (40ml) was added tert-butyl-chloro-dimethylsilane (3.25g, 21.55 mmol). The reaction mixture was stirred at room temperature overnight. DCM was added and the organic layer was washed with aqueous saturated NaHCO₃The solution is washed. The separated organic phase was dried (MgSO)₄) Filtering andand the organic layers were combined and evaporated in vacuo. The crude product was purified by flash column chromatography (eluent: EtOAc/heptane from 0/100 to 20/80). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 3.01g of intermediate 23 (49%).

Example A10

Preparation of intermediate 24

Sodium hydride (60% dispersion in mineral oil) (2.92g, 72.98mmol) was added to a mixture of 6-chloropyridine-2-carboxylic acid (5g, 31.73mmol), benzyl alcohol (4.27ml, 41.25mmol) in dry THF (250 ml). The reaction mixture was stirred at reflux for 48 h. The reaction mixture was poured into water and extracted with EtOAc (2 × 75 ml). The aqueous layer was acidified to pH 2 with aqueous HCl 37% solution and extracted with DCM (2 × 100 mL). The separated organic phase was dried (MgSO)₄) The organic layers were combined and evaporated in vacuo to afford a solid which was triturated with heptane. Yield: 6g of intermediate 24 (82%) as a white solid.

Example A11

a) Preparation of intermediate 25

Thionyl chloride (223ml, 3.07mol) was added dropwise to ice-cooled 5-bromo-2-pyridinecarboxylic acid (207g, 1.02mol) in MeOH (1.51). After the addition was complete, the reaction mixture was stirred at reflux for 3 h. The reaction mixture was cooled to room temperature and evaporated in vacuo. The residue was triturated with MeCN/DIPE. Yield: 180.3g of intermediate 25 (81%) as a white solid.

b) Preparation of intermediate 26

Trifluoroacetic anhydride (150ml, 1.08mol) was added dropwise to an ice-cooled mixture of intermediate 25(114g, 0.53mol), urea hydrogen peroxide (105g, 1.12mol) in MeCN (0.71) while maintaining the internal T below 10 ℃. The reaction mixture was allowed to reach room temperature and stirring was continued for 2 days. The reaction mixture was poured into 0.5M HCl solution (11) and extracted with DCM (2 × 0.31). The separated organic phase was dried (MgSO)₄) Filtered and the organic layers were combined and evaporated in vacuo. Yield: 120g of intermediate 26 (98%) as a pale yellow oil.

c) Preparation of intermediate 27

Trifluoroacetic anhydride (295ml, 2.12mol) was added dropwise to an ice-cooled mixture of intermediate 26(120g, 0.52mol) in DMF (11) while maintaining the internal T below 10 ℃. The reaction mixture was allowed to reach room temperature and stirring was continued for 16 hours. The reaction mixture was evaporated in vacuo. The residue was treated with water (0.51) and DCM (11). The separated organic phase was washed with brine (0.51). The separated organic phase was dried (MgSO)₄) The organic layers were filtered and combined and evaporated in vacuo to give a slurry oil, which was treated with water (0.21). The off-white precipitate was collected by filtration and dried. Yield: 62.5g of intermediate 27 (52%) as an off-white solid.

d) Preparation of intermediate 28

Lithium hydroxide (1.48g, 0.062mol) in water (30ml) was added all at once to intermediate 27(13g, 0.056mol) in THF (100 ml). The reaction mixture was stirred at 60 ℃ for 3 days. The reaction mixture was evaporated in vacuo and co-evaporated with MeCN (3 × 50 ml). Yield: 12.5g of intermediate 28 (99%) as an off-white solid.

Example A11

a) Preparation of intermediate 29

Thionyl chloride (23ml, 0.32mol) was added dropwise to ice-cooled 6-bromo-2-pyridinecarboxylic acid (12.23g, 0.061mol) in MeOH (100 ml). After the addition was complete, the reaction mixture was stirred at reflux for 16 h. The reaction mixture was cooled to room temperature and evaporated in vacuo. The residue was taken up with DCM and saturated NaHCO₃The solution is processed. The separated organic phase was dried (MgSO)₄) Filtered and the organic layers were combined and evaporated in vacuo. Yield: 10g of intermediate 29 (94%) as a white solid.

b) Preparation of intermediate 30

Intermediate 29(3g, 0.017mol), 3, 5-bis (trifluoromethyl) phenylboronic acid (5g, 0.019mol), potassium carbonate in DMF (50ml) (5g, 0.036mol) were loaded in a tube and flushed with nitrogen. Pd (PPh) was then added₃)₄(1g, 0.87 mmol). The reaction mixture was stirred at 160 ℃ for 1 h. The reaction mixture was cooled, poured onto ice water (0.11) and extracted with DIPE (3 × 0.11). The combined organic layers were washed with brine (0)11) treatment, drying (MgSO)₄) Filtered and evaporated in vacuo. The crude product was purified by flash column chromatography (eluent: DCM/heptane from 30/70 to 50/50). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 4g of intermediate 30 (65%) as a white solid.

c) Preparation of intermediate 31

The hydrogenation bottle was filled with platinum (IV) oxide (200mg, 0.88mmol) under nitrogen. Intermediate 30(2.8g, 0.008mol) in AcOH (20ml) was added and the flask was flushed with hydrogen. This procedure was repeated three times and then stirring was initiated until hydrogen uptake had ceased. The reaction mixture was filtered through a small plug of celite. The filtrate was evaporated in vacuo. The residue was diluted with DCM (0.11) and treated with 1M NaOH solution until pH 7. The aqueous layer was extracted with DCM (2 × 50 ml). The combined organic layers were dried (MgSO)₄) Filtered and evaporated in vacuo. The crude product was purified by flash column chromatography (eluent: DCM/heptane from 30/70 to 100/0). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 2g of intermediate 31 as an oil solidified to a white solid (70%) when it was left to stand.

d) Preparation of intermediate 32

Starting from intermediate 31, intermediate 32 was prepared by using a similar reaction scheme as described for intermediate 31.

Example A12

a) Preparation of intermediate 33

HBTU (1.27g, 3.36mmol) was added portionwise to a stirred solution of intermediate 28(752mg, 3.36mmol), DIPEA (1.58ml, 9.17mmol) in DMF (60ml) cooled with an ice/EtOH bath under nitrogen. The mixture was stirred at room temperature for 1 h. Intermediate 19(1g, 3.06mmol) in DMF (60ml) cooled with an ice/EtOH bath was added dropwise to the above solution. The reaction mixture was stirred at room temperature for 24 h. HBTU (900mg, 2.37mmol) was then added and the reaction mixture was stirred at room temperature for 24 h. The solvent was evaporated in vacuo. The residue was taken up in aqueous saturated NaHCO₃The solution (150ml) was diluted and extracted with EtOAc (250 ml). The combined organic layers were dried (MgSO)₄) Filtered and evaporated in vacuo. The crude product was purified by flash column chromatography (eluent: EtOAc/DCM from 2/98 to 5/95). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 900mg of intermediate 33 (58%).

b) Preparation of intermediate 34a/34b

Starting from intermediate 24 and intermediate 23, intermediate 34a and intermediate 34b were prepared by using a similar reaction scheme as described in example a12. a). The crude product was purified by flash column chromatography (eluent: EtOAc/heptane from 0/100 to 20/80). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 1.19g of intermediate 34a (26%) and 1.47g of intermediate 34b (33%).

c) Preparation of intermediate 35a/35b

Starting from intermediate 24 and intermediate 22, intermediate 35a and intermediate 35b were prepared by using a similar reaction scheme as described in example a12. a). The crude product was purified by flash column chromatography (eluent: EtOAc/heptane from 0/100 to 40/60). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 1g of intermediate 35a (38%) and 0.52g of intermediate 35b (20%).

Example A13

a) Preparation of intermediate 39

Intermediate 20(450mg, 1.32mmol) and intermediate 27(275mg, 1.19mmol) were stirred at 170 deg.C-180 deg.C under nitrogen for 3 h. The reaction mixture was cooled and dissolved in DCM. The crude product was purified by flash column chromatography (eluent: EtOAc/DCM from 2/98 to 5/95). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 300mg of intermediate 39 (43%).

b) Preparation of intermediate 40

Starting from intermediate 32 and intermediate 27, intermediate 40 (a mixture of 6aR, 10S and 6aS, 10R) was prepared by using a similar reaction scheme aS described in example a 13.a).

Example A14

a) Preparation of intermediate 41a

Tetrabutylammonium fluoride trihydrate (0.88g, 2.79mmol) was added to a solution of intermediate 34a (1.19g, 1.86mmol) in THF (6 mL). The reaction mixture was stirred at room temperature for 2 h. Water was added and the aqueous phase was extracted with EtOAc. The crude product was purified by flash column chromatography (eluent: MeOH/DCM from 0/100 to 5/95). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 739mg of intermediate 41a (76%) as a yellow solid.

b) Preparation of intermediate 41b

Starting from intermediate 34b, intermediate 41b was prepared by using an analogous reaction scheme as described in example a 14.a).

Example A15

a) Preparation of intermediate 42a

Palladium (10% wt) on activated carbon (wet, Degussa Type) (74mg) was added to a suspension of intermediate 41a (739mg, 1.41mmol) in MeOH (6ml) at 0 ℃. The reaction mixture was hydrogenated at 1 atmosphere at room temperature for 2 h. The reaction mixture was filtered through a pad of celite and washed with EtOH. The filtrate was evaporated in vacuo. The crude product was purified by flash column chromatography (eluent: EtOAc/DCM from 0/100 to 30/70). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 612mg of intermediate 42a (99%) as a yellow solid.

b) Preparation of intermediate 42b

Starting from intermediate 41b, intermediate 42b was prepared by using an analogous reaction scheme as described in example a 15.a).

Example A16

a) Preparation of intermediate 43a

Triphenylphosphine (554mg, 2.11mmol) and diisopropyl azodicarboxylate (0.42ml, 2.11mmol) were added to a solution of intermediate 42a (612mg, 1.41mmol) in THF (5ml) at 0 deg.C. The reaction mixture was stirred at room temperature. The solvent was evaporated under vacuum. The crude product was purified by flash column chromatography (eluent: EtOAc/heptane from 0/100 to 80/20). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 468mg of intermediate 43a (80%) are obtained as a white solid.

b) Preparation of intermediate 43b

Starting from intermediate 42b, intermediate 43b was prepared by using an analogous reaction scheme as described in example a 16.a).

Example A17

a) Preparation of intermediate 44a

Bromine (69ul, 1.35mmol) was added dropwise to a stirred solution of intermediate 43a in DCM (4ml) and AcOH (1ml) under nitrogen. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with saturated aqueous NaHCO₃The solution was diluted and extracted with DCM. The combined organic layers were dried (MgSO)₄) Filtered and evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc/hexanes from 0/100 to 50/50). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 300mg of intermediate 44a (54%) as a pale yellow solid.

b) Preparation of intermediate 44b

Starting from intermediate 43b, intermediate 44b was prepared by using an analogous reaction scheme as described in example a 17.a).

Example A18

a) Preparation of intermediate 45a

Thionyl chloride (0.14ml, 1.92mmol) was added to a stirred solution of intermediate 35a (0.8g, 1.74mmol) in DCM (20ml) under nitrogen at 5 ℃. The reaction mixture was stirred at room temperature for 2 h. The mixture was washed with saturated aqueous NaHCO₃The solution was diluted and extracted with DCM. The separated organic phase was dried (MgSO)₄) Filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (EtOAc/DCM from 0/100 to 50/50). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 0.43g of intermediate 45a (51%) and 0.25g of intermediate 47b (40%) as a colourless oil.

b) Preparation of intermediate 46b

Boron tribromide (0.26mL, 2.71mmol) was added to a solution of intermediate 45a (0.43g, 0.9mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 4 hours. Addition of saturated aqueous NaHCO₃Solution and MeOH. The reaction mixture was extracted with EtOAc and DCM. The separated organic phase was dried (MgSO)₄) Filtered and the solvent evaporated in vacuo. Yield: 0.32g of intermediate 46a (92%).

c) Preparation of intermediate 47a

Sodium hydride (60% dispersion in mineral oil) (0.049g, 1.24mmol) was added to a stirred solution of intermediate 46a (0.32g, 0.83mmol) in DMF (20mL) at 0 ℃ under nitrogen. The mixture was stirred at room temperature for 45 min. The reaction mixture was diluted with water and extracted with EtOAc. The separated organic phase was dried (MgSO)₄) Filtered and the solvent evaporated in vacuo. Yield: 0.29g of intermediate 47a (100%) as a colourless oil.

d) Preparation of intermediate 48a

Starting from intermediate 47a, intermediate 48a was prepared by using a similar reaction scheme as described for intermediate 47 a.

B. Preparation of the Compounds

Example B1

a) Preparation of Compound 1

In a first vial equipped with a magnetic stir bar and a screw-top septum, Pd is introduced₂(dba)₃A solution of (38mg, 0.042mmol) and 2-di-tert-butylphosphine-3, 4, 5, 6-tetramethyl-2 ', 4', 6 '-triisopropyl-1, 1' -diphenyl (40mg, 0.083mmol) in 1, 4-dioxane (1.6ml) and toluene (7.8ml) was flushed with nitrogen and stirred at 120 ℃ for 3 min. A second vial equipped with a magnetic stir bar and screw cap septum was filled with 4-methylimidazole (188mg, 2.29mmoL) and potassium phosphate (884mg, 4.16mmoL) followed by intermediate 33(1.060g, 2.08 mmoL)]) Filled and also flushed with nitrogen. The premixed catalyst solution was added to the second vial by syringe. The reaction mixture was heated at 120 ℃ for 5 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (50 ml). The organic phase was washed with brine (30 ml). The separated organic phase was dried (MgSO)₄) Filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (eluent: MeOH/DCM from 1/99 to 3/97). The product fractions were collected and the solvent was evaporated in vacuo. Yield: 400mg of Compound 1 (37%).

a) Preparation of Compound 2, Compound 3, Compound 4 and Compound 5

Compound 1(930mg) was purified by preparative SFC in (c)Daicel OD20x 250mm) into its four stereoisomers. Mobile phase (CO)₂Having 0.2% iPrNH₂MeOH) to yield 148mg of compound 2(3R, 11aR) or (3S, 11aS), 115mg of compound 3(3S, 11aR) or (3R, 11aS), 138mg of compound 4(3S, 11aS) or (3R, 11aR) and 127mg of compound 5(3R, 11aS) or (3S, 11 aR).

Example B2

a) Preparation of Compound 6

Starting from intermediate 39, compound 6 was prepared according to the procedure as described for compound 1.

a) Preparation of compound 7, compound 8, compound 9 and compound 10

Compound 6(1.44g) was purified by preparative SFC in (A)Daicel OD20x 250mm) into its four stereoisomers. Mobile phase (CO)₂Having 0.2% iPrNH₂MeOH) to yield 221mg of compound 7(6aR, 10R) or (6aS, 10S), 217mg of compound 8(6aS, 10R) or (6aR, 10S), 242mg of compound 9(6aS, 10S) or (6aR, 10R) and 190mg of compound 10(6aS, 10S) or (6aR, 10R).

Example B3

a) Preparation of Compound 11

Starting from intermediate 40, compound 11((6aR, 10S) and a mixture of (6aS, 10R)) was prepared according to the procedure aS described for compound 1.

b) Preparation of Compound 12 and Compound 13

Compound 11(400mg, 40% purity) was prepared by preparative SFC in (A)Daicel OD20x 250mm) into the corresponding enantiomer. Mobile phase (CO)₂Having 0.2% iPrNH₂MeOH) to yield 21mg of compound 12(6aR, 10S) or (6aS, 10R) and 19mg of compound 13(6aS, 10R) or (6aR, 10S).

Example B4

a) Preparation of Compound 14

Starting from intermediate 44a, compound 14 ((mixture of (3R, 11aR) and (3S, 11aS)) was prepared aS described for compound 1.

b) Preparation of Compound 15 and Compound 16

Compound 14(140mg) was prepared by preparative SFC in (A), (B), (C), (Daicel OD20x 250mm) into the corresponding enantiomer. Mobile phase (CO)₂Having 0.2% iPrNH₂MeOH) to yield 120mg of compound 15(3R, 11aR) and 5mg of compound 16(3S, 11 aS).

Example B5

a) Preparation of Compound 17

Starting from intermediate 44b, compound 17 ((mixture of (3R, 11aS) and (3S, 11aR)) was prepared aS described for compound 1.

b) Preparation of Compound 18 and Compound 19

Compound 17(225mg) was prepared by preparative SFC in (A), (B), (C), (Daicel OD20x 250mm) into the corresponding enantiomer. Mobile phase (CO)₂Having 0.2% iPrNH₂MeOH) to yield 5mg of compound 18(3R, 11aS) and 160mg of compound 19(3S, 11 aR).

Example B6

Preparation of Compound 20 and Compound 21

4-methylimidazole (0.069g, 0.84mmol), cesium carbonate (0.27g, 0.84mmol) and cuprous iodide (0.016g, 0.084mmol) were added to a solution of intermediate 48a (0.18g, 0.42mmol) in DMF (5ml) (previously deoxygenated). Nitrogen was bubbled through the reaction mixture for 5min, after which the reaction mixture was heated in a sealed tube at 120 ℃ under nitrogen for 12 h. Water and EtOAc were added. The organic layer was separated and the aqueous layer was extracted with EtOAc. The organic phase was washed with brine. The separated organic phase was dried (MgSO)₄) Filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (eluent: MeOH/DCM from 0/100 to 3/97). The product fractions were collected and subjected to vacuumThe solvent is evaporated. The residue was triturated with MeOH/DIPE and purified by preparative HPLC on (LUNA 5U C18(2) 100A). Mobile phase (5mM NH)₄OAc/MeCN 90/10). The residue was dissolved with DCM and washed with water. The separated organic phase was dried (MgSO)₄) Filtered and the solvent evaporated in vacuo to yield 8mg of compound 20(3R, 11aR) and 5mg of compound 21(3S, 11 aR).

The compounds listed in table 1 have been prepared.

No.' means compound number. The absolute stereochemical arrangements for compounds 15-16, 18-19 and 20-21 were performed by NMR.

TABLE 1

Analysis section

LCMS(liquid chromatography/Mass Spectrometry)

High Performance Liquid Chromatography (HPLC) measurements were performed using LC pumps, Diode Arrays (DADs) or UV detectors and columns as specified in the corresponding methods. Additional detectors were included if necessary (see method table below).

The flow from the column is brought to a Mass Spectrometer (MS) equipped with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set tuning parameters (e.g. scan range, residence time, etc.) in order to obtain ions of nominal monoisotopic Molecular Weight (MW) that allow identification of compounds. Data acquisition is performed using appropriate software.

Retention time (R) by experiment_t) And an ion describing compound. If not specified differently in the data sheet, the reported molecular ion corresponds to [ M + H [ ]]⁺(protonated molecules) and/or [ M-H]^-(deprotonated molecules). For molecules with multiple isotopic patterns (e.g., Br or Cl), the reported values are those obtained for the lowest isotopic mass. All results obtained have experimental uncertainties typically associated with the methods used.

Hereinafter, "SQD" means single quadrupole detector, "BEH" means bridged ethylsiloxane/silica hybridization, "DAD" means diode array detector, "HSS" means high intensity silica, and "ELSD" means evaporative light scanning detector.

Table 2: LCM method code (flow in mL/min; column temperature in deg.C (Col T); run time in minutes)

Melting Point

Melting points (m.p.) were determined with DSC823e or DSC1 (Mettler-Toledo) and measured with a temperature gradient of 10 ℃/min.

The results of the analytical measurements are shown in table 2 a.

Table 2 a: retention time (R)_t) In min, [ M + H [ ]]⁺Peak (protonated molecule), LCMS method and m.p. (melting point in ° c). n.d. indicates no determination

NMR

For a plurality of compounds, inChloroform-d (deuterated chloroform, CDCl) was used on a Bruker AvanceIII with 300MHz super-shielded magnet, on a Bruker DPX-400 spectrometer operating at 400MHz, on a Bruker DPX-360 operating at 360MHz, or on a Bruker Avance 600 spectrometer operating at 600MHz₃) Or DMSO-d₆(deuterated DMSO, dimethyl-d 6 sulfoxide) as solvent¹H NMR spectrum. Chemical shift () is reported in parts per million (ppm) relative to Tetramethylsilane (TMS) (used as an internal standard).

Table 2 b:¹results of H NMR

SFC-MS

For SFC-MS, an analytical SFC system from bergel Instruments (Berger Instruments) was used, which system included a system for delivering CO₂And a dual pump control module (FCM-1200) of modifiers with a thermal control module (TCM2100) for column heating with temperature control in the range of 1-150 ℃ and column selection valves (walco, VICI, houston, TX, USA) for 6 different columns. Photodiode array detector (Agilent 1100, Waltburon, Germany) equipped with a high voltage flow cell (up to 400 bar) and with a CTC LC Mini PAL autosampler (Lei @)Subscience Inc. (leap technologies), Roche, NC, USA). A ZQ mass spectrometer (Watts, Millford, Mass., USA) with a vertical Z-electrospray interface was connected to the SFC-system. An integrated platform consisting of SFC ProNTo software and Masslynx software is used for instrument control, data collection and processing.

Compound No. 2-5: SFC-MS was performed on an OD-H column (250X 4.6mm) (Daicel Chemical Industries Ltd.) at a flow rate of 3 ml/min. Two mobile phases (mobile phase A: CO) are used₂(ii) a Mobile phase B: containing 0.2% iPrNH₂iPrOH) of (2). 50% B was held for 25 min. The column temperature was set at 30 ℃. Under these conditions, compound No. 2 eluted first from the column, compound No. 3 eluted second from the column, compound No. 5 eluted third from the column, and compound No. 4 had the longest retention time on the column (R)_t). The measured values were compared with a mixture of these 4 compounds.

Compound No. 7-10: SFC-MS was performed on an OD-H column (250X 4.6mm) (Daicel Chemical Industries Ltd.) at a flow rate of 3 ml/min. Two mobile phases (mobile phase A: CO) are used₂(ii) a Mobile phase B: containing 0.2% iPrNH₂MeOH) of (c). Hold 25% B for 15 min. The column temperature was set at 30 ℃. Under these conditions, compound No. 7 eluted first from the column, compound No. 9 eluted second from the column, compound No. 10 eluted third from the column, and compound No. 8 had the longest retention time on the column (R)_t). The measured values were compared with a mixture of these 4 compounds.

Compound No. 12-13: SFC-MS was performed on an OD-H column (250X 4.6mm) (Daicel Chemical Industries Ltd.) at a flow rate of 3 ml/min. Two mobile phases (mobile phase A: CO) are used₂(ii) a Mobile phase B: containing 0.2% iPrNH₂MeOH) of (c). First 20% B was held for 18.5 min. Then after 3min a gradient was applied from 20% B to 50% B and 50% B was held for 3.1 min. The column temperature was set at 30 ℃. Under these conditions, the compounds are encodedNumber 12 had a shorter retention time (R) than Compound No. 13_t)。

Compound No. 15-16: SFC-MS was performed on an AD-H column (250X 4.6mm) (Daicel Chemical Industries Ltd.) at a flow rate of 3 ml/min. Two mobile phases (mobile phase A: CO) are used₂(ii) a Mobile phase B: containing 0.2% iPrNH₂EtOH) of (ii). A gradient was applied from 10% B to 40% B after 18.75min first. A gradient was then applied from 40% B to 50% B after 2min, and 50% B was held for 3.6 min. The column temperature was set at 30 ℃. Under these conditions, compound No. 15 had a shorter retention time (R) than compound No. 16_t)。

Compound nos. 18-19: SFC-MS was performed on an AD-H column (250X 4.6mm) (Daicel chemical industries Ltd.) at a flow rate of 3 ml/min. Two mobile phases (mobile phase A: CO) are used₂(ii) a Mobile phase B: containing 0.2% iPrNH₂EtOH) of (ii). A gradient was applied from 10% B to 40% B after 18.75min first. A gradient was then applied from 40% B to 50% B after 2min, and 50% B was held for 3.6 min. The column temperature was set at 30 ℃. Under these conditions, compound No. 18 had a shorter retention time (R) than compound No. 19_t)。

Pharmacology of

A) Screening of Compounds of the invention for Gamma-secretase-modulating Activity

Screening was performed using hAPP 695-wild type SKNBE2 human neuroblastoma cells grown to near confluency in Dulbecco's Modified Eagle's Medium/Nutrient mixture F-12(DMEM/NUT-mix F-12) (HAM) (catalog No. 10371-029) supplied by Invitrogen (Invitrogen), containing 5% serum/Fe supplemented with 1% non-essential amino acids, 1-glutamine 2mM, Hepes 15mM, penicillin 50U/ml (units/ml) and streptomycin 50. mu.g/ml.

Using as in ceterolong, etcHuman (1997) Natural Medicine (Nature Medicine) 3: 67 for screening. Briefly, cells were plated at 10⁴The cells/well were placed in a 384-well plate from Ultrafiltration (Lonza, BE12-725F) supplemented with 1% glutamine (Invitrogen, 25030-024), 1% non-essential amino acids (NEAA), penicillin 50U/ml in streptomycin 50. mu.g/ml in the presence of test compounds at various test concentrations. The cell/compound mixture was incubated at 37 ℃ with 5% CO₂Incubate overnight. The next day, the medium was assayed by two sandwich immunoassays for a β 42 and total a β.

Total Α β and Α β 42 concentrations were quantified in cell supernatants using the Aphalisa technique (Perkin Elmer). α lisa is a sandwich assay using biotinylated antibodies attached to streptavidin-coated donor beads and antibodies that bind to acceptor beads. In the presence of antigen, these beads become in close proximity. Excitation of the donor bead causes the release of singlet oxygen molecules, which triggers a cascade of energy transfers in the acceptor bead, resulting in light emission. To quantify the amount of a β 42 in the cell supernatant, a monoclonal antibody specific for the C-terminus of a β 42(JRF/cA β 42/26) was coupled to the acceptor beads and a biotinylated antibody specific for the N-terminus of a β (JRF/a β N/25) was used to react with the donor beads. To quantify the total a β amount in the cell supernatant, a monoclonal antibody specific for the N-terminus of a β (JRF/a β N/25) was coupled to the acceptor beads and a biotinylated antibody specific for the middle region of a β (biotinylated 4G8) was used to react with the donor beads.

To obtain the values reported in table 3, the data were calculated as a percentage of the maximum amount of amyloid β 42 measured in the absence of the test compound. Nonlinear regression analysis was used to analyze sigmoidal dose-response curves plotted as percent of control versus log concentration of compound. IC determination using a4 parameter equation₅₀。

Table 3: ("n.d." means undetermined)

B) Demonstration of in vivo efficacy

B-1)Aβ42

The Α β 42-lowering agents of the present invention may be used to treat AD in mammals (such as humans) or, alternatively, demonstrate efficacy in animal models such as, but not limited to, mice, rats or guinea pigs. The mammal may not be diagnosed as having AD, or may not have a genetic susceptibility to AD, but may be transgenic such that it overproduces and eventually deposits a β in a manner similar to that seen in humans suffering from AD.

The a β 42 lowering agent can be administered in any standard form using any standard method. For example, but not limited to, the a β 42 lowering agent may be in the form of a liquid, tablet or capsule that is taken orally or by injection. The a β 42-lowering agent can be administered in any dose sufficient to significantly reduce the level of a β 42 in blood, plasma, serum, cerebrospinal fluid (CSF), or brain.

To determine whether acute administration of an a β 42-lowering agent will reduce a β 42 levels in vivo, non-transgenic rodents, e.g., mice or rats, are used. Animals treated with a β 42-lowering agents were examined and compared to those untreated or treated with vehicle, and brain levels of soluble a β 42, a β 40, a β 38, and a β 37 were quantified by MSD (Meso Scale Discovery) electrochemiluminescence detection techniques. The treatment period varies from hours (h) to days and is adjusted based on the results of the a β 42 reduction once the onset time course of the effect can be established.

A typical experimental protocol for measuring a β 42 reduction in vivo is shown, but this is but one of many variants that can be used to optimize detectable levels of a β. For example, the A.beta.42 lowering compound is formulated to 20% in water(sulfobutyl ether of beta-cyclodextrin) or 20% hydroxypropyl beta cyclodextrin. These a β 42-lowering agents are administered to overnight fasted animals in a single oral dose or by any acceptable route of administration. After 4h, the animals were sacrificed and analyzed for a β 42 levels.

Blood was collected in EDTA-treated collection tubes by decapitation and exsanguination. Blood was centrifuged at 1900g for 10 minutes (min) at 4 ℃ and plasma was recovered and flash frozen for subsequent analysis. The brain was removed from the skull and hindbrain. The cerebellum was removed and the left and right hemispheres were separated. The left hemisphere was stored at-18 ℃ for quantitative analysis of test compound levels. The right hemisphere was rinsed with Phosphate Buffered Saline (PBS) buffer and immediately frozen on dry ice and stored at-80 ℃ until homogenized for biochemical determination.

Mouse brains from non-transgenic animals are resuspended in 8 volumes of 0.4% DEA (diethylamine)/50 mM NaCl per gram of tissue containing protease inhibitors (Roche) -11873580001 or 04693159001), e.g. 1.264ml of 0.4% DEA is added for 0.158g of brain. All samples were homogenized in the FastPrep-24 system (MP biomedical Inc. (MP Biomedicals)) using lysis matrix D (MPBio # 6913-. The homogenate was centrifuged at 20800x g for 5min and the supernatant collected. The supernatant was centrifuged for 50min at 221.300x g. The resulting high-speed supernatant was then transferred to a new microcentrifuge tube (eppendorf). Nine supernatants were neutralized with 1 part of 0.5M Tris-HCl (pH 6.8) and used to quantify A β.

To quantify the amount of a β 42, a β 40, a β 38 and a β 37 in the soluble fraction of brain homogenate, simultaneous specific detection of a β 42, a β 40, a β 38 and a β 37 was performed using the electrochemiluminescence multiplexing technique of MSD. In this assay, purified monoclonal antibodies specific for A β 37(JRD/A β 37/3), A β 38(J & JPRD/A β 38/5), A β 40(JRF/cA β 40/28), and A β 42(JRF/cA β 42/26) were coated on MSD 4-plex plates. Briefly, standards (dilutions of synthetic a β 42, a β 40, a β 38 and a β 37) were prepared in 1.5ml microcentrifuge tubes from Ultraculture, with final concentrations ranging from 10000 to 0.3 pg/m. Samples and standards were incubated with Sulfo-tagged JRF/rA β/2 antibody (labeled at the N-terminus of A β as detector antibody). Then 50 μ l of conjugate/sample or conjugate/standard mixture was added to the antibody coated plate. The plate was allowed to incubate overnight at 4 ℃ to allow formation of antibody-amyloid complexes. The assay was completed by adding read buffer (read buffer) after this incubation and subsequent washing steps according to the manufacturer's instructions (msandong (Meso Scale Discovery), Gaitherburg, MD).

The sulflo-TAG emits light when electrochemical stimulation from the electrode occurs. The MSD sector meter SI6000 was used for signal readout.

In this mode, a β 42 reduction is advantageous compared to untreated animals, in particular having an a β 42 reduction of at least 10%, more in particular having an a β 42 reduction of at least 20%.

B-2)Aβ38

The Α β 38 increasing agents of the present invention may be used to treat AD in mammals (such as humans) or, alternatively, demonstrate efficacy in animal models such as, but not limited to, mice, rats or guinea pigs. The mammal may not be diagnosed as having AD, or may not have a genetic susceptibility to AD, but may be transgenic such that it overproduces and eventually deposits a β in a manner similar to that seen in humans suffering from AD.

The a β 38 increasing agent may be administered in any standard form using any standard method. For example, but not limited to, the a β 38 increasing agent may be in the form of a liquid, tablet or capsule that is taken orally or by injection. The a β 38 increasing agent may be administered in any dose sufficient to significantly increase the level of a β 38 in blood, plasma, serum, cerebrospinal fluid (CSF), or brain.

To determine whether acute administration of an a β 38 increasing agent will increase a β 38 levels in vivo, non-transgenic rodents, e.g., mice or rats, are used. Animals treated with a β 38 increasing agent were examined and compared to those untreated or treated with vehicle, and brain levels of soluble a β 42, a β 40, a β 38, and a β 37 were quantified by MSD electrochemiluminescence detection techniques. The treatment period varies from hours (h) to days and is adjusted based on the results of the increase in a β 38 once the onset time course of the effect can be established.

A typical experimental protocol for measuring the increase in a β 38 in vivo is shown, but this is only one of many variants that can be used to optimize detectable a β levels. For example, the A β 38 increasing agent is formulated to 20% in water(sulfobutyl ether of beta-cyclodextrin) or 20% hydroxypropyl beta cyclodextrin. These a β 38 increasing agents are administered to overnight fasted animals in a single oral dose or by any acceptable route of administration. After 4h, the animals were sacrificed and analyzed for a β 38 levels.

To quantify the amount of a β 42, a β 40, a β 38 and a β 37 in the soluble fraction of brain homogenate, simultaneous specific detection of a β 42, a β 40, a β 38 and a β 37 was performed using the electrochemiluminescence multiplexing technique of MSD. In this assay, purified monoclonal antibodies specific for A β 37(JRD/A β 37/3), A β 38(J & JPRD/A β 38/5), A β 40(JRF/cA β 40/28), and A β 42(JRF/cA β 42/26) were coated on MSD 4-plex plates. Briefly, standards (dilutions of synthetic a β 42, a β 40, a β 38 and a β 37) were prepared in 1.5ml microcentrifuge tubes from Ultraculture, with final concentrations ranging from 10000 to 0.3 pg/m. Samples and standards were incubated with Sulfo-tagged JRF/rA β/2 antibody (labeled at the N-terminus of A β as detector antibody). Then 50 μ l of conjugate/sample or conjugate/standard mixture was added to the antibody coated plate. The plate was allowed to incubate overnight at 4 ℃ to allow formation of antibody-amyloid complexes. The assay was completed by adding read-out buffer after this incubation and subsequent washing steps according to the manufacturer's instructions (majordomo, gaithersburg, MD).

In this mode, an increase in a β 38 compared to untreated animals is advantageous, in particular with an a β 38 increase of at least 10%, more in particular with an a β 38 increase of at least 20%.

B-3) results

The results are shown in table 4 (dose 30mg/kg administered orally) (values for untreated animals as control (Ctrl) are set at 100):

prophetic composition examples

The "active ingredient" (a.i.) as used throughout these examples relates to a compound of formula (I), including any tautomer or stereoisomeric form thereof, or a pharmaceutically acceptable addition salt or solvate thereof; specifically to any of the exemplified compounds.

Typical examples of formulations for the formulations of the present invention are as follows:

1. tablet formulation

2. Suspension liquid

An aqueous suspension for oral administration is prepared so as to contain 1 to 5mg of the active ingredient, 50mg of sodium carboxymethylcellulose, 1mg of sodium benzoate, 500mg of sorbitol and water to 1ml per ml.

3. Injectable preparation

A parenteral composition is prepared by stirring 1.5% (weight/volume) of the active ingredient in a 0.9% NaCl solution or in a 10% by volume aqueous solution of propylene glycol.

4. Ointment

In this example, the active ingredient may be replaced by the same amount of any of the compounds according to the invention, in particular by the same amount of any of the exemplified compounds.

Claims

1. A compound of formula (I)

A tautomer or a stereoisomeric form thereof, wherein

R¹Is phenyl, naphthyl, indolyl, benzothienyl, benzothiazolyl, or benzofuranyl;

each optionally with one, two or three of each independentlySubstituted with a substituent selected from the group consisting of: halogen and C optionally substituted with one, two or three halogen substituents_1-4An alkyl group;

l is attached to position a or b;

y is-Q- (CH)₂)_m-、-CH₂-Q-CH₂-、-(CH₂)_n-、

One of them being-CH₂-by hydroxy and C_1-4Alkyl substituted- (CH)₂)_n-, or

One of them being-CH₂-substituted by one hydroxy group- (CH)₂)_n-；

n represents 1,2 or 3;

m represents 1 or 2;

q is O or NR⁶；

R⁶Is hydrogen or C_1-4An alkyl group;

R²is hydrogen, halogen or C_1-4An alkyl group;

R³is hydrogen or C_1-4An alkyl group;

R⁴is hydrogen, halogen or C_1-4An alkyl group;

x is CR⁵Or N;

R⁵is hydrogen or C_1-4An alkyl group;

or a pharmaceutically acceptable addition salt or a solvate thereof.

2. The compound of claim 1, wherein

R¹Is phenyl, naphthyl or indolyl;

each optionally substituted with one, two, or three substituents each independently selected from the group consisting of: halogenAn element and C optionally substituted with one, two or three halogen substituents_1-4An alkyl group;

l is attached to position a;

y is-Q- (CH)₂)_m-、-CH₂-Q-CH₂-、-(CH₂)_n-、

One of them being-CH₂-by hydroxy and C_1-4Alkyl substituted- (CH)₂)_n-, or

One of them being-CH₂-substituted by one hydroxy group- (CH)₂)_n-；

n represents 1,2 or 3;

m represents 1 or 2;

q is O or NR⁶；

R⁶Is hydrogen or C_1-4An alkyl group;

z is methylene;

R²is hydrogen;

R³is hydrogen or C_1-4An alkyl group;

R⁴is hydrogen, halogen or C_1-4An alkyl group;

x is CH.

3. The compound of claim 1, wherein

l is attached to position a;

l is selected from the group consisting of: covalent bond and-C_1-6Alkanediyl-;

y is- (CH)₂)_n-；

n represents 1 or 2;

z is methylene;

R²is hydrogen;

R³is hydrogen;

R⁴is C_1-4An alkyl group;

x is CR⁵；

R⁵Is hydrogen.

4. The compound of claim 1, wherein

L is a covalent bond or-C_1-6An alkanediyl group-.

5. The compound of claim 1, wherein

R¹Is phenyl substituted with one, two or three substituents each independently selected from the group consisting of: halogen and C substituted by one, two or three halogen substituents_1-4An alkyl group.

6. The compound of claim 1, wherein

Z is methylene.

7. The compound according to claim 1, wherein the compound is

A tautomeric or stereoisomeric form thereof,

Or a pharmaceutically acceptable addition salt thereof, or a solvate thereof.

8.A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound according to any one of claims 1 to 7.

9. A compound as defined in any one of claims 1 to 7 for use as a medicament.

10. A compound as defined in any one of claims 1 to 7 for use in the treatment or prevention of a disease or condition selected from: alzheimer's disease, traumatic brain injury, mild cognitive impairment, aging, dementia with Lewy bodies, cerebral amyloid angiopathy, multi-infarct dementia, dementia pugilistica, Down's syndrome, dementia associated with Parkinson's disease and dementia associated with beta-amyloid.

11. A compound according to claim 10, wherein the disease is alzheimer's disease.

12.A method of treating or preventing a disease or disorder selected from: alzheimer's disease, traumatic brain injury, mild cognitive impairment, senility, dementia with lewy bodies, cerebral amyloid angiopathy, multi-infarct dementia, dementia pugilistica, down syndrome, dementia associated with parkinson's disease and dementia associated with beta-amyloid, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 7 or a therapeutically effective amount of a pharmaceutical composition according to claim 8.

13. The method according to claim 12, wherein the disease is alzheimer's disease.

14.A method of treating or preventing a disease or disorder selected from: neurocognitive disorder due to alzheimer's disease, neurocognitive disorder due to traumatic brain injury, neurocognitive disorder due to lewy body disease, neurocognitive disorder due to parkinson's disease or vascular neurocognitive disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 7 or a therapeutically effective amount of a pharmaceutical composition according to claim 8.

15.A compound as defined in any one of claims 1 to 7 for use in the treatment or prevention of a disease or condition selected from: a neurocognitive disorder due to Alzheimer's disease, a neurocognitive disorder due to traumatic brain injury, a neurocognitive disorder due to Lewy body disease, a neurocognitive disorder due to Parkinson's disease, or a vascular neurocognitive disorder.